Prostaglandins and Other Lipid Mediators 164 (2023) 106698

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Prostaglandins and Other Lipid Mediators

journal homepage: www.elsevier.com/locate/prostaglandins

Lipoxin and glycation in SREBP signaling: Insight into diabetic

cardiomyopathy and associated lipotoxicity
Muskan Thakur, Rashmi S. Tupe *
Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University) (SIU), Lavale, Pune 412115, Maharashtra State, India

A R T I C L E I N F O A B S T R A C T

Keywords: Diabetes and cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Diabetes in­
Diabetic cardiomyopathy creases cardiovascular risk through hyperglycemia and atherosclerosis. Chronic hyperglycemia accelerates gly­
Lipid metabolism cation reaction, which forms advanced glycation end products (AGEs). Additionally, hyperglycemia with
Glycation
enhanced levels of cholesterol, native and oxidized low-density lipoproteins, free fatty acids, and oxidative stress
Lipoxin
SREBP signaling
induces lipotoxicity. Accelerated glycation and disturbed lipid metabolism are characteristic features of diabetic
heart failure. SREBP signaling plays a significant role in lipid and glucose homeostasis. AGEs increase lipotoxicity
in diabetic cardiomyopathy by inhibiting SREBP signaling. While anti-inflammatory lipid mediators, lipoxins
resolve inflammation caused by lipotoxicity by upregulating the PPARγ expression and regulating CD36. PPARγ
connects the bridge between glycation and lipoxin in SREBP signaling. A summary of treatment modalities
against diabetic cardiomyopathy is given in brief. This review indicates the novel therapeutic approach in the
crosstalk between glycation and lipoxin in SREBP signaling.

1. Introduction systolic and diastolic dysfunctions, thereby causing diabetic cardiomy­

Cardiovascular diseases (CVDs) impact a significant part of the
global population, with a 31.4% death rate from 50% of global mortality
caused due to non-communicable diseases cumulatively [1]. Most recent
figures show the logarithmic increase in the mortality rate due to CVDs
which was 18.6 million in 2019, indicating that CVDs are a global topic
of concern [2]. Various risk factors and stimulators increase the severity
of CVDs; one of them is diabetes, a highly prevalent disease worldwide
[3,4]. Globally, CVDs affect approximately 32.2% of persons with type 2
diabetes mellitus [5]. Likewise, type 2 diabetes is associated with a
2–4-fold increase in the risk of sudden cardiac arrest or heart failure [6].
One of the significant risk factors of diabetic-CVDs is glycation, a reac­
tion between the carbonyl group of reducing sugar in the bloodstream
and the free amino group of proteins and lipids occurring during chronic
hyperglycemia [7–9]. It gives rise to various advanced glycation end
products (AGEs), having receptor-dependent and independent effects on
cells. AGEs disrupt extracellular matrix proteins’ structural, functional,
and enzymatic properties and hamper their degradation, leading to
opathy (DCM) [4]. They also activate multiple intracellular signaling
pathways and trigger inflammation [10].
Uninterrupted cardiac muscle contraction needs high energy inputs
from biomolecules like carbohydrates, lipids, proteins, ketones, and
fatty acids [11]. Lipids are the most abundant source of energy for the
heart as the normal heart generates about 70–90% ATP from fatty acid
oxidation [12] (Fig. 1). Moreover, lipids serve many critical roles in
biological systems as they are the signaling molecules, substrates for
β-oxidation, and target moieties for post-translational protein modifi­
cations [13]. Various lipid mediators produced from arachidonic acid
have a wide range of therapeutic advantages (discussed later in this
review) in DCM. Importantly, α, β- polyunsaturated lipid aldehydes act
as lipid electrophiles that modify lipids, proteins, and nucleic acids [14].
A heart can switch its substrate selection based on the energy demand to
cope with critical physiological and pathological conditions. Disturbed
metabolism of cardiac energy is the primary characteristic of a failing
heart where in pathological situations, impaired insulin signaling,
lipolysis, and fatty acid release from adipose tissue are augmented

Abbreviations: CVDs, Cardiovascular diseases; DCM, Diabetic cardiomyopathy; LDL, Low-density lipoprotein; Ox-LDL, Oxidized LDL; AGEs, Advanced glycation
end products; RAGE, Receptor for AGEs; SREBP, Sterol regulator element binding protein; LX, Lipoxin; LO, Lipoxygenase; ROS, Reactive oxygen species; CD36,
Cluster of differentiation 36; PPARγ,, Peroxisome proliferator-activated receptors gamma.
* Corresponding author.
E-mail address: rashmi.tupe@ssbs.edu.in (R.S. Tupe).

https://doi.org/10.1016/j.prostaglandins.2022.106698
Received 26 September 2022; Received in revised form 8 November 2022; Accepted 10 November 2022
Available online 13 November 2022
1098-8823/© 2022 Elsevier Inc. All rights reserved.
M. Thakur and R.S. Tupe Prostaglandins and Other Lipid Mediators 164 (2023) 106698

Fig. 1. Glucose and fatty acid metabolism in a healthy heart. In cardiomyocytes, glucose and free fatty acids are taken in through their respective receptors, CD36
and GLUT4. In the cytosol, acetyl CoA is produced from free fatty acids, and glucose produces pyruvate through glycolysis. Once pyruvate is transported to the
mitochondria, it produces acetyl CoA. On the other hand, the carnitine receptor facilitates the transport of long-chain fatty acids into mitochondria where it is
modified to acetyl-CoA on β-oxidation. Acetyl-CoA produced from fatty acid and glucose metabolism makes FADH2 and NADH through the TCA cycle and generates
ATP after entering into ETC, thereby, maintaining cardiac energy metabolism. Abbreviations: CoA, coenzyme A, TCA, tricarboxylic acid cycle; FADH2, Flavin adenine
dinucleotide; NADH, nicotinamide adenine dinucleotide; ECT, electron transport chain; ATP, adenosine triphosphate; CPT-1, carnitine palmitoyltransferase-1; CD36,
cluster of differentiation 36; ACS, acyl-CoA synthetases; CACT, carnitine-acylcarnitine translocase; CPT-2, carnitine palmitoyltransferase-2; MPC, mitochondrial
pyruvate carrier; ADP, adenosine diphosphate; GLUT4, glucose transporter type 4.

[15–17]. A decrease in the oxidation rate of fatty acids and more reli­
ability to glycolysis for ATP generation indicate impaired cardiac
functioning. Disturbed substrate switch and selection are also mainly
associated with deleterious consequences [18]. Gradually, the heart gets
used to the rapid adoption of fatty acids for ATP generation. Chronic
situations often fatigue the left ventricle for adequate cardiac output and
lead to DCM [19] (Fig. 2).
Due to the great importance of lipid metabolism in DCM and other
metabolic disorders, researchers are keen to explore signaling molecules
or lipid mediators associated with the pathogenesis of DCM. Recently, it
has been reported that sarcolemmal substrate transporters for fatty
acids, glucose transporter type 4, and a cluster of differentiation 36
(CD36) play a crucial role in cardiac energy metabolism [20], as they
can shift lipid metabolism to lipotoxicity. Thus, they can be targeted for
metabolic modulation therapy against DCM. Inspecting CD36 levels can
regulate cardiac energy, lipid metabolism and repair cardiac contrac­
tions [21]. Upregulated expression of CD36 was found in the diabetic
heart; later, it was discussed that miR-320 could suppress CD36 tran­
scriptions and improve cardiac functions [22]. In the context of
miR-320, Li and colleagues have explained how miR-320 induces car­
diac lipotoxicity by enhancing CD36 gene expressions [23]. Their
research showed upregulated miR-320 expressions in the nucleus of
cardiomyocytes of db/db mice and diabetic hearts from patients with
cardiac dysfunctions, suggesting the role of miR-320 as a small acti­
vating RNA at the transcriptional level. Also, CD36 was found to be the
target gene of this miRNA. As a result, the translocation of miR-320 to
the nucleus upregulated CD36 expressions, disrupting cardiac lipid
metabolism. Thus, the miR-320/CD36 pathway was summarized to link
glucose toxicity to lipotoxicity in diabetic hearts. Similarly, another
study described miR-320 as a late-responding miRNA that exacerbates
apoptosis and cardiac dysfunctions in the diabetic milieu, concluding
that knocking out miR-320 would be an effective treatment strategy
against DCM [24]. Furthermore, cumulative pieces of evidence indi­
cated that cardiac lipotoxicity could affect heart functions through
modulating miRNA profiling as they can limit senescence (miR-195),
regulate microvascular complications (miR-93), decrease fibrosis and
vascular permeability (miR-200a-3p, miR-200b) and help the patients to
recover from hyperglycemia, diabetes mellitus, and associated diabetic
complications. However, many other miRNAs are linked with the dis­
ease progression (miR-351 [25], miR-34a, miR-146, miR-195, etc.). This
hints that miRNAs can be explored more in DCM-related pathogenesis
[26].
While research continues to study lipid metabolism through various
aspects, this review revises the role of lipid metabolism in yet another set
of inflammation mediators of DCM. Our work focuses on glycation,
hampered lipid metabolism in DCM, cellular signaling events, and the
lipid mediators involved in DCM pathogenesis. This review also dis­
cusses the need for translation studies, a lab-to-bed approach, with po­
tential therapeutics for improved or novel diagnostic or prognostic
biomarkers for alleviating DCM.
1.1. Multifactorial etiology of CVDs in diabetes
One of the drastic consequences of diabetes is CVDs. In addition to
biochemical pathways connecting diabetes to CVDs, some lifestyle-
related factors also take part in diabetes leading to CVDs [27].

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M. Thakur and R.S. Tupe
Fig. 2. Disturbed cardiac energy metabolism leading to the DCM. Impaired
glucose and fatty acid metabolism enhance cardiac overload and pressure
through oxidation, and metabolic inflammation, leading to cardiac hypertro­
phy, contractile dysfunctions, and, ultimately, DCM. Abbreviation: ATP, aden­
osine triphosphate.
Fig. 3. Factors associating diabetes with CVD. Formation of AGEs in hyperglycemia, promotion of atherosclerosis and dyslipidemia, macrovascular defects,
endothelial dysfunction, leukocyte recruitment and aggregation, augmented oxidative stress, and mitochondrial dysfunction is some of the paramount factors
participating in DCM pathogenesis. In addition, ruptured plaque leads to thrombotic cell death resulting in insufficient inflammatory resolution.
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Prostaglandins and Other Lipid Mediators 164 (2023) 106698
Multiple factors associated with diabetes participate in CVDs patho­
genesis; some are illustrated in Fig. 3.
1.1.1. Aging and senescence
It is also believed that the prevalence of diabetes increases with
aging. It is the most common incidence in adults aged 65 years and older
[28]. Aging is responsible for reduced insulin sensitivity in patients with
diabetes. Age-associated elevated visceral adiposity results in high levels
of pro-inflammatory cytokines in the blood that interfere with insulin
signaling [29]. Insulin resistance in people with diabetes impairs lipid
uptake and storage, leading to elevated plasma levels of atherogenic
low-density lipoprotein (LDL), causing CVDs-associated mortality [30].
The aging of cells in a diabetic milieu triggers senescence [31]. Type 2
diabetes is often described as a disease of premature immunosenescence
with a loss of naïve CD4+ and CD8+ T cells with elevated late-stage T cell
differentiation [32–34]. In 2019, it was demonstrated that senescent T
cells cause hyperglycemia and inflammation [34,35], involving cardiac
hypertrophy, fibrosis, arterial stiffness, altered calcium signaling,
mitochondrial and endothelial dysfunctions, excess reactive oxygen
species (ROS) generation, impaired cell signaling [36]. Studies have
shown senescence accumulation in most cardiac cell populations that
modifies cell phenotypes and enhances inflammation, ending in heart
failure in the diabetic population [37,38].
1.1.2. Sex difference and body mass index
There are well-established differences between women and men in
terms of epidemiology, pathophysiology, effects of treatment therapies,
and clinical outcomes [39]. These differences are called sex differences
due to differential gene expression from sex chromosomes and the car­
diovascular system. It is established that ovulating women without
diabetes experience significantly lower cardiovascular incidences than
diabetic women and men, hinting at the role of estrogen hormone in
reducing CVDs events [40]. However, in the diabetic population, men
are twice, and females are five times at risk of developing CVDs
compared to the general population [41]. Women show end-systolic
ventricular pressures at a much higher rate than men [39]. This sug­
gests that estrogen replacement therapy may help ameliorate CVDs.
M. Thakur and R.S. Tupe
However, clinical studies have challenged this notion [42–45]. On the
other hand, body mass index is tightly associated with a higher risk of
diabetes mellitus, hypertension, and CVDs. Increased risk of diabetes
and associated cardiac complications were observed at higher BMI levels
in men than in women [46]. A higher body mass index defines obesity,
the apparent reason behind diabetes and CVDs related mortality.
Obesity can participate in low-grade systemic inflammation, abrupt
immune response, maladaptive immune metabolism, and cytokine
release, further developing cardiac hypertrophy, fibrosis, and cardio­
myopathy [47,48].
1.1.3. Atherosclerosis and dyslipidemia
Diabetes can align itself with the state of chronic, low-level inflam­
mation where increased ROS production in hyperglycemia accelerates
the process of atherosclerosis, a focal, progressive, and stable disease
where arterial lesions are caused. Diabetes may only have one pathway
to cause atherosclerosis which is dyslipidemia. It is highly related to
diabetes pathogenesis, as 97% of patients who have diabetes are dysli­
pidemic [49,50]. These lesions are promoted by LDL and the accumu­
lation of fatty substances, calcium, cholesterol, and fibrin, which fill up
the inner lining of the arteries or other vessel walls and block the
oxygenated blood flow to the heart and other body parts. The de­
positions build up over time and narrow the arterial diameter [51]. As
the atherosclerotic plaques grow, they come in contact with circulating
platelets. As a result, platelets get aggregated into the atherosclerotic
plaque, ultimately leading to thrombotic cell death. Due to increased
ROS production, hyperactive platelets also elevate inflammation and
thrombosis [52]. Atherosclerosis might cause problems like angina,
strokes, or myocardial infarctions. The plaques form in the smaller ar­
teries causing microvascular disorder [53]. Macrovascular defects
caused due to diabetes in CVDs mainly focus on atherosclerosis. One of
the prominent LDL-cholesterol in atherosclerosis is its small and dense
form. They can bond strongly with extracellular adhesion molecules
[54]. They are more susceptible to oxidation and can penetrate the
arterial wall and accelerate atherosclerosis. Oxidized LDL (ox-LDL) is
more prone to acquire new properties and is considered “foreign” by the
immune system [55]. Structural and functional modifications in ox-LDL
attract leukocytes to the injured endothelial. Leukocytes’ enhanced
ability to take up ox-LDL promotes their differentiation into foam cells
[56].
Contrastingly, high-density lipoproteins are known for their athe­
roprotective nature as they perform reverse cholesterol transport. In this
process, cell cholesterol is removed by efflux to apoproteinA-I and high-
density lipoprotein as extracellular acceptors, transporting the choles­
terol to the liver for excretion or its utilization in the form of bile acids
[57].
1.1.4. Inflammatory cytokines
Activation of multiple intracellular pathways, including NF-κB dur­
ing diabetes and CVDs, facilitates the secretion of pro-inflammatory
cytokines. As soon as cytokines are released from the inflamed cells,
leukocytes get activated and start accumulating at the injury site. Acti­
vated leukocytes also produce ROS in excess, anchoring the activation of
inflammatory pathways and contributing to CVDs pathophysiology
[58]. This immune response from leukocytes enhances chronic inflam­
mation conditions when incoming leukocytes cannot dispose of the site
of inflammation, injuring endothelial cells. Accelerated cytokine secre­
tion from inflamed endothelial enhances the lipolysis of adipocytes.
Increased lipolysis increases the levels of circulating free fatty acids that
deposit in the target tissues [59]. Abnormal levels and metabolism of
lipids, fatty acids, cholesterol, and other metabolites present around the
cells help in the secretion of inflammatory cytokines (C-reactive protein,
plasminogen activator inhibitor-1, interleukin-1β, etc.) and activate
monocytes, which later turn into foam cells, accelerating atheroscle­
rosis, myocytes’ stiffness and scarring, thus leading to DCM. Increased
secretion of cytokines often enhances insulin resistance in diabetic
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Prostaglandins and Other Lipid Mediators 164 (2023) 106698
individuals [60], progressing to various diabetic complications such as
DCM.
1.1.5. ROS production, lipid metabolism, and mitochondrial stress
Small changes or modifications in lipids’ location or composition can
significantly affect cell functions and their survival. Oxidative stress
occurs when the cellular environment becomes excessively oxidized
because of ROS overproduction. Enhanced oxidative stress in diabetes
can directly damage lipids and promotes their lipid peroxidation, which
has various effects on cellular functions, such as increased apoptosis,
decreased autophagy, disturbed cell proliferation, transcriptional
deregulation [14,61], enhanced oxidative stress-mediated inflammatory
signaling and leukocytes activation, cytokine secretion and chronic
inflammation, leading to DCM.
Almost all cell organelles produce ROS, and mitochondria generating
hydrogen peroxide is believed to be the primary source of oxidants [62].
High glucose flux in diabetes helps in excess ROS generation, enhancing
mitochondrial dysfunction [63]. Furthermore, hyperglycemia-induced
mitochondrial ROS has been found to accelerate almost all the path­
ways by which hyperglycemia causes diabetic complications, such as
protein kinase C activation, positive regulation of hexosamine, and
polyol pathways [58]. A class of cytotoxic lipids directly affects mito­
chondrial stress, resulting in cell apoptosis. In the inner mitochondrial
membrane, bisphosphatidyl glycerol phospholipid cardiolipin is local­
ized which is highly susceptible to lipid peroxidation and generates
hydroperoxides, one of them is 4-hydroxynonenal, known for disrupting
mitochondria and their functioning [64,65]. 4-hydroxynonenal also acts
as a signaling molecule and regulates several signaling pathways
involved in oxidative stress, cell proliferation, senescence, autophagy,
apoptosis, and necrosis, such as nuclear factor erythroid 2-related factor
2, activating protein-1, NF-κB, and peroxisome-proliferator-activated
receptors (PPAR) [66]. In addition, the oxidation of cardiolipin can
hamper the activity of complexes I and IV, leading to impaired mito­
chondrial respiration and energy production. Reduced cardiolipin and
its oxidation mediated-mitochondrial dysfunction are well connected
with CVDs pathogenesis, diabetes, atherosclerosis, and many more
metabolic disorders [67].
1.1.6. ROS production, lipid metabolism, and endoplasmic reticulum stress
The endoplasmic reticulum is the primary cellular organelle for
synthesizing lipids, protein folding and maturation, and calcium ho­
meostasis [68]. A significant part of the integral and secretory proteins
translocate into the endoplasmic reticulum lumen as it provides space
and environment for posttranslational protein modifications and their
foldings [69]. Misleading endoplasmic reticulum functioning causes
oxidative stress, disturbed calcium homeostasis, ischemia, and over­
expression of misfolded proteins, leading to endoplasmic reticulum
stress and activation of unfolding protein response. Such a response
either halts further posttranslational stage of misfolded proteins or ac­
tivates signaling pathways to produce molecular chaperons that correct
protein folding. If nothing happens, this response switches on apoptotic
signaling, playing an essential role in DCM [70,71]. Li et al. (2007)
showed the interference of endoplasmic reticulum stress in the apoptosis
of cardiomyocytes in streptozotocin-induced diabetic rats [72]. Studies
have pointed out a close association between endoplasmic reticulum
stress and dysregulated lipid metabolism in various cells having meta­
bolic importance [73]. Other studies have shown that the crosstalk be­
tween hyperglycemia-induced glycation and oxidative stress can
progress diabetes, CVDs, and eventually DCM [74]. Thus, targeting the
endoplasmic reticulum and oxidative stress induced by glycation in the
diabetic milieu can ameliorate diabetes-induced cardiac remodeling and
cardiomyopathy.
2. Glycation and lipid metabolism: digging deep into DCM
Glycation is the crucial player in DCM pathogenesis as it causes
M. Thakur and R.S. Tupe Prostaglandins and Other Lipid Mediators 164 (2023) 106698

Fig. 4. Glycation reaction leading to DCM. AGEs, through their receptor-dependent or independent actions, hamper extracellular matrix proteins’ structural and
functional properties. It also disturbs glucose and lipid metabolism, and together these defects lead to DCM. Abbreviations: AGEs, advanced glycation end products;
RAGE, receptor for AGEs; ECM, extracellular matrix.

Table 1
Various types of AGEs associated with DCM.
Classification of AGEs Examples Role in DCM References

Cytotoxicity
Classification based on the
type of structure and the
origin of the substrates
Toxic Crosslinking AGEs Vesperlysine, Pentosidine, Crossline, Increased vascular and myocardial stiffness, [79]
AGEs with fluorescence MRX, Vesper lysine A, GOLD, MOLD, endothelial dysfunction, atherosclerotic plaque
GOLDIC, MOLDIC, glucosepane. formation
Non-fluorescent IDL, Alkyl formyl glycosyl pyrrole,
cross-linking Arginine lysine imidazole,
Glucosepane
Non- Noncross-linking and Pyrraline, Argpyrimidine, MG- The amount of CML significantly increased in the [80]
toxic nonfluorescent AGEs imidazolones, 3-DG-imidizolones, arterial wall of AGE-albumin-treated animals. Even in
AGEs GA-pyridine, CML, CEL, FL the absence of DM, AGEs triggered atherogenesis in
dyslipidemic mice.
Modified protein HbA1c, Type IV collagen, crystalline, Exhibits a slow turnover rate of about ten years. It [81]
apo B100, accumulates with a yearly rate of about 3,7%,
reaching a 30–50% increase at 80 years of age.
Low molecular AGEs Pyralline, CML, CEL, Pentosidine, Biomarker of tissue amine modification linked to the [82]
Imidazole presence of (unmeasured) toxic molecules with cross-
linking potential or the ability to activate specific AGE
receptors
Produced from a particular AGE-1, AGE-2, AGE-3, AGE-4, AGE-5, Interaction of angiogenic bone marrow cells with [83]
glycating agent AGE-6, AA-AGE AGE-modified collagen results in reduced cell
adhesion, increased susceptibility to apoptosis, fewer
progenitor cells, and reduced angiogenic potential.

Abbreviations: AGEs (advanced glycation end-products), MRX (Maillard reaction product X), GOLD (glyoxal lysine dimmer), MOLD (methylglyoxal lysine dimer), IDL
(imidazolium dilysine), AFGP (alkyl formyl glycosyl pyrrole), ALI (arginine lysine imidazole), MG-imidazolones (methylglyoxal-imidazolones), 3-DG-imidizolones (3-
deoxyglucosone-imidizolones), GA-pyridine (gallic acid-pyridine), CML (N-carboxymethyllysine), CEL (N-carboxyethyl-lysine), FL (N-fructosyl-lysine), apoB100
(apolipoprotein B100), HbA1c (Hemoglobin A1c), AGE-1 (glucose-derived AGEs), AGE-2 (glyceraldehyde-derived AGEs), AGE-3 (glycoaldehyde derived AGEs), AGE-4
(Methylglyoxal-derived AGEs), AGE-5 (glyoxal-derived AGEs), AGE-6 (3-deoxyglucosone-derived AGEs), AA-AGE (acetaldehyde-derived AGEs)

atherogenesis by maintaining the stability of atherosclerotic plaques,
mainly by AGEs formation [75]. Different AGEs have inflammatory ef­
fects on DCM through either receptor or non-receptor-mediated path­
ways (Fig. 4) [10]. Glycation of apoprotein B and LDL leads to functional
disruption and turns their momentums towards oxidation, forming
glyoxal, glycol-aldehydes, and other carbonyl intermediates. The
carbonyl compounds further interact with extracellular matrix proteins
and form AGEs (e.g., imidazolone, N-carboxymethyl lysine,
N-carboxyethyl-lysine, methylglyoxal lysine dimer, glyoxal lysine dim­
mer) [53]. These AGEs are principal cardiometabolic risk factors.
AGEs-induced lipid accumulation is correlated with autophagy; cells
encourage autophagy before lipid accumulation, which is how glycation
induces cell death [76]. AGEs interfere with native proteins and can
resist their expected degradation via intracellular proteasomal complex,
thereby elevating oxidative stress inside or outside the cardiomyocytes
[77]. This alters the permeability of the extracellular matrix and traps

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M. Thakur and R.S. Tupe Prostaglandins and Other Lipid Mediators 164 (2023) 106698

Fig. 5. Biosynthesis of LXs and their epimers in inflammation settings. Glycation and disrupted lipid metabolism-induced inflammation stimulates cardiomyocyte’s
membrane phospholipids and facilitate the release of arachidonic acid by the cytosolic phospholipase 2 enzyme, producing LXs and their isomers via LO and COX-2
pathways. Abbreviations: AGEs, advanced glycation end products; RAGE, receptor for AGEs; LDL, low-density lipoprotein; CD36, cluster of differentiation 36; ROS,
reactive oxygen species; cPLA2, cytosolic phospholipase A2; LO, lipoxygenase; 15(s)-HETE, 15(s)- hydroxyeicosatetraenoic acid; 15(R)-HETE, 15(R)- hydrox­
yeicosatetraenoic acid; COX 2, cycloxygenase 2; FLAP, 5-lipoxygenase activating protein; LTA4, leukotriene 4; LTB4, LTC4, leukotriene cysteinyl 4; LX, lipoxin.

the macromolecules against the vessel wall. As a result, the extracellular
matrix releases inflammatory cytokines and growth factors, enhancing
the endothelium’s antithrombotic properties and the vessel wall’s abil­
ity to modulate vascular tone, leading to low-grade inflammation
associated with DCM [78]. Table 1 summarizes the involvement of
various glycation adducts in DCM pathogenesis.
2.1. Receptor-mediated pathways of AGEs
The most dominant AGEs receptors in DCM pathogenesis are the
receptors for AGEs (RAGE) with different isoforms, namely, soluble
RAGE and endogenous secretory RAGE [84]. Soluble RAGE circulates in
the blood system, and its elevated levels are associated with the
increased risk of DCM in diabetes mellitus patients [85]. Thus, they can
be considered an indicator of the destabilization of vulnerable plaque.
High RAGE levels are commonly seen in any inflammatory lesion,
including those found in blood vessel walls [84,86], indicating the
importance of the AGEs-RAGE axis as a therapeutic target for DCM
amelioration. AGEs and their receptors have inflammatory effects,
including endothelial dysfunction, smooth muscle cell proliferation and
migration, macrophage activation, atrial stiffness, mitochondrial and
cytoskeletal dysfunction, enhanced ROS formation, impaired calcium
homeostasis, atherosclerosis, enhanced uptake of ox-LDL, accelerated
foam cell formation, contributing to abnormal lipid metabolism and
regulating DCM pathogenesis [87]. Upregulated RAGE is often associ­
ated with granular calcification, which exposes the lipid core of
atherosclerotic plaques and favors its rupture [88], thus, initiating in­
flammatory responses through lipid deposit-induced
metalloproteinases.
3. Lipoxins in DCM
The immune system releases anti-inflammatory molecules and cy­
tokines in response to inflammation [89]. Lipoxins (LXs) are
anti-inflammatory lipid mediators secreted by various immune cells,
including neutrophils and macrophages [90]. LXs come from non-classic
eicosanoids and are members of the specialized pro-resolving mediators
family of polyunsaturated fatty acid metabolites, arachidonic acid [91].
LXs cast an anti-inflammatory and pro-resolving effect on many cells and
are supposed to be associated with the suppressed cell injuries mediated
by inflammatory leukocytes [92,93], leading to reduced proin­
flammatory cytokines release and production. They first came into the
light of research when Serhan et al. isolated them from human leuko­
cytes [90]. They are described as unsaturated molecules having an
anti-inflammatory activity against various metabolic diseases, including
atherosclerosis and CVDs. Still, little is known about their mechanism of
action in glycation and glycation-induced DCM.
3.1. Synthesis and mode of action of LXs
LXs are synthesized by interactions with lipoxygenase (LO) products
produced from arachidonic acid metabolism. They are generated as a
response to the cell-cell interactions at the site of injury and host re­
sponses to inflammation or infection [94]. This review hypothesizes that
glycation-induced inflammation can act as the stimulator for releasing
arachidonic acid leading to LXs synthesis (Fig. 5). Arachidonic acid
further synthesizes LXs through two pathways by three major LO, viz.
5-LO, 15-LO, and 12-LO, (i) the first route involves a series of actions of
LO in monocytes and neutrophils, where arachidonic acid is converted
to 15(s)- hydroxyeicosatetraenoic acid, one of the stereoisomers of 15-
hydroxyeicosatetraenoic acid, which further produces LXs, (ii) the sec­
ond route takes place in platelets where leukotriene A4 acts with 12-LO
and forms LXs (iii) Aspirin leads an additional route of LXs synthesis
with the help of which their epimers are formed. Aspirin acetylates
cyclooxygenase-2 and forms 15(R)- hydroxyeicosatetraenoic acid,
another stereoisomer of 15- hydroxyeicosatetraenoic acid [90]. In the
end, LXs and their epimers are generated through 5(s), 6(s), 15(s)-
epoxytetraeneoic acid intermediate [87]. It is to be noted that various
important pro- and anti-inflammatory molecules are generated during
the production of LXs, giving therapeutic directions to arachidonic acid

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M. Thakur and R.S. Tupe Prostaglandins and Other Lipid Mediators 164 (2023) 106698

Table 2 hydroxyeicosatetraenoic acid formed by the action of 5-, 12- and 15-LO
Different types of LXs and their biological roles in CVDs. has been suggested to have hypertrophic effects on human ventricular
Sr. Role of LXs in CVDs Study Model References cardiomyocytes; the hypertrophic activity was shown to be MAPK- and
No. NF-κB dependent [98]. Arachidonic acid metabolism via the cyclo­
LXA4 & LXB4
oxygenase pathway generates a family of prostanoid mediators having
1. Resolve atherosclerotic Apolipoprotein E deficient [92, pro-inflammatory activities in DCM pathogenesis. Thromboxanes are
plaques and increase mice 111–115]
plaque stability
such prostanoid mediators, which are potential vasoconstrictors and
2. Recruit non-inflammatory Primary Human Umbilical [111,116, platelet aggregates. They hamper the metabolism of extracellular matrix
monocytes to Vein Endothelial Cells 117] proteins and promote fibrosis and scarring. They also enhance the
inflammatory sites, functioning of lymphocytes and macrophages, directing immunomod­
suppress neutrophil
ulatory effects in DCM [99]. However, the actions of cycloxygenase
chemotaxis, adhesion &
transmigration, diminish metabolites are complex, and certain prostanoids (prostaglandins,
P-selectin-mediated prostacyclin) inhibit immune and inflammatory responses associated
neutrophil-endothelial with DCM. Therefore, it is hypothesized that non-steroidal anti-in­
interactions, flammatory drugs are supposed to inhibit inflammatory prostanoids like
3. Reduce oxLDL cholesterol Patients who underwent [111,118,
and foam cell formation coronary angiography for 119]
thromboxane.
chest pain
LXA4, 15-epi-LX4 3.1.2. Anti-inflammatory molecules in LXs biosynthesis
4. Reduce reperfusion- Human leukocytes [111], On the other side, a metabolite from the arachidonic acid pathway
associated vascular [120]
formed from cytochrome P450 monooxygenases and epoxygenases is
inflammation
5. Reduce pro-inflammatory TNF-α-initiated neutrophil [111,116, epoxyeicosatrienoic acid, which has the potential to restore cardiac
cytokine secretion and (polymorphonuclear 121] remodeling and pro-inflammatory cytokine secretion [100]. A review
ROS production leukocyte) responses in vitro from Romashko and colleagues has postulated that epoxyeicosatrienoic
and in vivo using acid promotes vasodilation, anti-inflammatory, and anti-apoptotic
metabolically stable LX
analogs
properties by reducing blood pressure, adiposity, and myocardial
6. Inhibit angiogenic Primary Human Umbilical [111,117, fibrosis [101]. In addition, it can also limit atherosclerosis and DCM,
pathways, including Vein Endothelial Cells 122–124] lowering heart failure incidences [102]. Prostaglandin E receptor sub­
endothelial cells type 4 acts via FOXO1/CD36 signaling and mediates cardiac uptake of
proliferation and
fatty acids and ATP generation, thus, protecting against DCM [103].
activation
LXA4 Evidence shows that disturbed prostaglandin D2 signaling enhances
7. Decrease monocyte IL-1β 15 patients with severe [111,125] atherosclerosis, hypertension, myocardial ischemia, and DCM patho­
& calcium efflux preeclampsia and 20 normal genesis [104]. Cycloxygenase-2 mediated increased prostaglandin E
pregnant women (control receptor subtype two syntheses in cardiac inflammation milieu suggests
group)
8. Modulate K+ channel and Rat cardiomyocytes [111,125,
the cardioprotective role of prostaglandin E2 in DCM [105–107]. Pros­
activate p38 MAPK 126] tacyclin is yet another inflammation mediator produced during arach­
pathways and nuclear idonic acid metabolism through cycloxygenase-2. A study showed a
translocation of NRF2; critical role of prostacyclin in cardiac inflammation by increased
induces the release of the
atherosclerosis and thrombosis with enhanced proliferative response to
protective heme
oxygenase-1 carotid vascular injury on knockout of prostacyclin receptor in mice
9. Decrease proliferation, Human and mouse B cells [111,127] [108].
IgG & IgM production of
human memory B-cells, 3.2. LXs in DCM and glycation
inhibiting NF-kB p65
nuclear translocation
10. A vasodilator promoting Wistar rats [128] Increased extracellular cholesterol levels cause the shifting of 15-lip­
the endothelial release of oxygenase to LDL oxidation and induce inflammation while negatively
prostacyclin and nitric regulating blood pressure. LXs and other pro-resolvins in human serum
oxide while inhibiting
can reverse this shift back to cholesterol [109]. LXs are shown to have
ROS production
anti-inflammatory actions, such as inhibited foam cell formation,
Abbreviations: oxLDL (oxidized low-density lipoprotein), TNFα (Tumor necrosis ox-LDL-induced inflammation, and apoptotic signaling in macrophages.
factor alpha), ROS (reactive oxygen species), IL-1β (interleukin − 1β), MAPK Table 2 enlists some such major bioactions of LXs in CVDs. Literature
(mitogen-activated protein kinase), Nrf2 (nuclear erythroid 2-related factor 2),
supports the hypothesis that LXs have therapeutic potential in
IgG (immunoglobulin G), IgM (immunoglobulin M), NF-kB (nuclear factor
diabetes-associated vascular complications [110].
Kappa-light-chain-enhancer of activated B cells)
LXs help combat atherogenesis by reducing fibroblast maturation,
collagen production, and myofibroblast differentiation; hence, they can
metabolic signaling.
be the target molecules as their actions may have therapeutic potential
in the treatment of diabetes-induced atherosclerosis, suggested the in-
3.1.1. Pro-inflammatory molecules in LXs biosynthesis
vivo study performed by Brennan and group [110]. This review points
LO activities can be associated with DCM pathogenesis as they
out that LXA4 has been extensively studied in various metabolic disor­
oxidize LDLs and triggers atherosclerosis [95]. 5-LO predominantly
ders such as atherosclerosis and CVDs. At the same time, LXA4 and
forms 5- hydroxyeicosatetraenoic acid and leukotrienes, which are
respective epimers are not well explored in glycation-associated meta­
involved in leukocyte recruitment, inflammatory cytokine production,
bolic diseases. This indicates the research potential of LXs and their
hampered vascular permeability, and endothelial dysfunction [95,96].
epimers in glycation-induced DCM.
Synthesis of leukotrienes requires a 5-LO activating protein, which as­
sembles other enzymes needed for leukotriene synthesis in leukocytes
3.3. LX-ALX/FPR2 receptor-mediated action
[97]. In this sense, inhibitors for 5-LO activating protein can have a
strong therapeutic potential in alleviating DCM. 15-
Lipid mediators LXs act via G-protein coupled receptors, namely

7
M. Thakur and R.S. Tupe Prostaglandins and Other Lipid Mediators 164 (2023) 106698

5-lipoxygenase, which is also involved in the PPARγ accelerating

Fig. 6. Scheme illustrating the connection of glycation and LXs in SREBP sig­
nalling. Glycation, LXs, and PPARγ expression regulate SREBP-1c signaling in
DCM through their specific mechanism of action. Regulation of SREBP-1c
expression by keeping a check on glycation-LXs crosstalk in glycation-induced
DCM can be a novel therapeutic approach. Abbreviations: AGEs, advanced
glycation end products; SREBP-1c, sterol regulatory element binding proteins-
1c, PPARγ, peroxisome proliferator-activated receptor gamma.
CD36 expression, is a precursor of LXs generation [144]. PPARγ and
5-lipoxygenase clear apoptotic neutrophils and limit inflammatory tis­
sue injury [145]. LXs upregulate the expression of CD36 independent of
PPARγ [144]. It also can upregulate PPARγ expression. All three entities,
glycation, LXs, and SREBPs, are well established with their respective
positive or negative effects on lipid metabolism, either leading to or
inhibiting DCM pathogenesis. However, glycation-induced inflamma­
tion can trigger LXs biosynthesis by immune cells; the LXs are not
studied in the glycation pathway to date, which can be a significant
therapeutic breakthrough against deteriorated lipid metabolism in
DCM. LXs and SREBP signaling are associated with lipid metabolism
and, when studied together, can be a vital tool for treating disrupted
immunometabolism in many metabolic disorders, including DCM.
Perhaps the literature lacks the interaction of LXs and SREBP signaling;
they both regulate PPARγ receptors in one way or another, showing the
potential of LXs in SREBP signaling in glycation-induced disrupted lipid
metabolism in DCM through these nuclear receptors (Fig. 6).
This review has already described the mechanism of action of gly­
cation and LXs in DCM. To understand their roles in SREBP signaling, it
is essential to know how the signaling works in cardiac energy
metabolism.
5. SREBP signaling in lipid metabolism

Transcription factors SREBPs are extensively involved in regulating

ALX/FPR2 [129,130]. It limits leukocyte trafficking and activation,
gene expressions in synthesizing lipids and function in global biological
stimulating efferocytosis, granulocyte apoptosis, and leukocyte egress
signaling pathways related to various physiological and pathophysio­
[130]. It also suppresses calcium-sensing kinase and
logical processes [146]. They are of three types with three different
calcium-calmodulin-dependent protein kinase and inhibits p38
established functions in lipid metabolism: (i) SREBP1a in global lipid
mitogen-activated protein kinase phosphorylation [131]. Failed
synthesis, (ii) SREBP1c in fatty acid synthesis and energy storage; (iii)
inflammation resolution in terms of increased pro-inflammatory ago­
SREBP2 involved in cholesterol regulation [147]. Pathways related to
nists and decreased levels of pro-resolving agonists in atherosclerosis
cholesterol synthesis and uptake are controlled via end-product feed­
was observed by a disrupted balance between ALX/FPR2 ligands [132].
back inhibition of 3-hydroxy-3- methylglutaryl CoA reductase at the
Hence, restoration of the pro-resolving ALX/FPR2 signaling with the
transcriptional level. 3-hydroxy-3- methylglutaryl CoA reductase is a
help of lipid or peptide agonists can be a novel therapeutic approach in
rate-limiting enzyme of cholesterol synthesis through LDLR, facilitating
atherosclerosis. Accelerating ALX/FPR2 signaling is essential in limiting
endocytosis of cholesterol-rich LDLs [148,149]. These genes have a
neutrophil-mediated ischemia, reperfusion injury, smooth muscle
sterol regulatory element (SRE) on their promoter region, regulating
cell-mediated intimal hyperplasia, and restenosis after different revas­
sterol-dependent expression regulation [150]. In their native form,
cularization procedures [133]. Also, there is an urgent need to study
SREBPs are manufactured and stored at the endoplasmic reticulum
ALX/FPR2 signaling in DCM and glycation-induced complications.
membrane. The active N-terminal of SREBPs needs to undergo proteo­
lytic cleavage to facilitate their transcriptional activities and nuclear
4. LXs and glycation in sterol regulating element binding
translocation. Nuclear cleavage depends on cellular cholesterol avail­
protein (SREBP) signaling
ability [146,150,151]. When cholesterol is low, SCAP binds to and es­
corts SREBP in COP II vesicles to the Golgi complex, where the SREBPs
Regulation of cardiac lipid metabolism is dominated by transcrip­
are cleaved by a serine protease, site 1, and zinc metalloprotease, site 2.
tional factors SREBPs [134,135]. A statin group of SREBP is responsible
Once the cholesterol level is restored, Insig, an endoplasmic reticulum
for blocking lipid generation by inhibiting the 3-hydroxy-3- methyl­
membrane protein regulator, traps and brings the SREBP/SCAP complex
glutaryl CoA pathway [136]. AGEs produced in glycation reactions can
to the endoplasmic reticulum. It controls SREBP cleavage in the Golgi,
increase lipid generation through activated SREBP cleavage-activating
thus, downregulating the LDL receptor biosynthesis [152]. They are
protein (SCAP)/SREBP signaling; SCAP is a functional cholesterol
strongly implicated in various pathological consequences, including
sensor [137].
inflammation, autophagy and apoptosis, and endoplasmic reticulum
Additionally, glycation has been shown to have an inversely pro­
stress, thereby contributing to obesity, dyslipidemia, diabetes, fatty liver
portional expression with peroxisome proliferator-activated receptors
disease, chronic kidney disease, neurodegenerative diseases, and can­
(PPARγ), nuclear receptors with active participation in lipid and glucose
cers [146]. As atherosclerosis, dyslipidemia, and cardiac metabolism are
homeostasis as transcriptional factors [138]. Upregulated PPARγ ex­
closely related and intertwined, it is necessary to study the SREBP
pressions showed AGEs-damaged chondrocyte repair in a study carried
signaling in glycation-induced DCM.
out in 2015 [139]. In another study, AGEs enhance the IL-1 and TNF-α
expressions and inhibit PPARγ in a time and dose-dependent manner
5.1. SREBPs and cardiac metabolism: Clinical prospective
[140]. Short-chain fatty acids and their derivatives help activate PPARγ
and create a lipid signaling network between the nucleus and cell sur­
Pathogenesis of DCM is multifactorial and involves cardiac immu­
face. Less PPARγ hampers adipose tissue’s ability to store fat, thereby
nometabolism [153]. During DCM, augmented cardiac lipid levels in­
increasing lipotoxicity and causing DCM [141,142]. PPARγ also en­
crease mitochondrial and endoplasmic reticulum stress [154]. The
hances the expression of CD36 and resolves inflammation [17].
functions of SREBPs are closely associated with the endoplasmic retic­
Furthermore, PPARγ positively regulates the expression of SREBP-1c; it
ulum. Chronic endoplasmic reticulum stress dysregulates SREBPs
enhances lipid oxidation and synthesis [143].
expression and enhances intracellular lipid levels [155]. A study

8
M. Thakur and R.S. Tupe
Table 3
Pharmacological interventions used in the treatment of CVDs.
Drug Class Associated drugs Mechanism of action
Calcium Channel Drug classification
Blockers or calcium Dihydropyridine derivative: High affinity for Ca+ channels in
agonists[166–168] Nifedipine, Nicardipine, vascular smooth muscle cells,
Nilvadipine, low membrane potential,
Phenylalkylamine derivative: increased activity in vessels than in
Verapamil cardiac muscle cells.
Benzodiazepine derivative:
Diltiazem
Diarylaminopropylamine Act on the impulse conduction system
derivative: with high membrane potential and Ca+
Bepridil channels in ventricular muscle,
adverse inotropic, chronotropic, and
dromotropic effects.
The intermediate effect between the
dihydropyridine and phenylalkylamine
derivatives,
act on the myocardium and impulse
conduction system, particularly in
atrioventricular node conduction
A long-acting, non-selective, significant
anti-anginal, antihypertensive,
selective anti-arrhythmia activity acts
as a calmodulin antagonist.
Sodium-glucose Drug classification
Cotransporter SGLT1[169] High-affinity, low-capacity glucose
inhibitors Sotagliflozin, Zynquista transporter is predominantly found in
enterocytes of the small intestine,
where it transports glucose and
galactose from the gut lumen across the
gut wall
SGLT2[170] Reduces reabsorption of filtered glucose
Canagliflozin, Ertugliflozin, from the tubular lumen and lowers the
Empagliflozin RTG
GLP-1 receptor Drug classification
agonists[171] Short-acting drugs[172]: Decreases glucagon release during
exenatide, lixisenatide, hyperglycemic periods, which reduces
semaglutide hepatic glucose output and decreases
insulin demand. Delayed gastric
emptying decreases the rate at which
glucose arrives in the bloodstream.
Long-acting drugs[172]: Delayed atherosclerosis progression by
Liraglutide[173] regulating inflammation through LDL
Semaglutide[173,174] receptor-deficient and apolipoprotein
Exenatide[175] E-deficient mice
Decreases systolic BP, body weight, and
blood glucose levels.
Improves insulin sensitivity and
intramyocellular lipid. Activates AMP-
activated protein kinase signaling
pathway without BW reduction
PCSK9 inhibitors Alirocuma,Evolocumab, Human IgG1 monoclonal antibody that
Bococizumab[176] binds and inhibits PCSK9
Anti-Advanced Aminoguanidine[177] Binds to sugars, thus preventing them
Glycation End from binding to the lysine group of
Products proteins. Prevent oxidative
Compounds modification of LDL and inhibit the
formation of atherosclerotic plaques
Benfotiamine[178] Post-Amadori inhibitor by trapping
dicarbonyl intermediates, inhibition of
NADPH oxidase
ACEIs (ex. captopril, enalapril, Pre & post-Amadori inhibitor,
lisinopril, ramipril) transition metal ion chelator
Statins Stimulates RAGE shedding and lowers
(Atorvastatin, fluvastatin, cholesterol in LDL, non-HDL, and RLP
lovastatin, pravastatin, and in the fasting and fed states
simvastatin)[179,180]
9
Prostaglandins and Other Lipid Mediators 164 (2023) 106698
Physiological actions Adverse effects References
The strong hypotensive effect, Excessive hypotension, edema,
strong coronary vasodilation, tachycardia reflex
strong peripheral vasodilation,
high cardiac contraction,
increased heart rate,
moderate atrioventricular
conduction
Strong coronary vasodilation, Vasoconstriction, hemostasis,
strong peripheral vasodilation, thrombosis, ischemia, seizures,
decreased cardiac contraction, hyperthermia, and rhabdomyolysis
moderate heart rate, Impaired muscle coordination
decreased atrioventricular
conduction
Extreme coronary vasodilation,
weak peripheral vasodilation,
decreased cardiac contraction,
decreased heart rate,
decreased atrioventricular
conduction
Significant coronary Urticaria, gastrointestinal
vasodilation, modest peripheral disturbances
effects
The putative intestinal target for Genital infections, diabetic
antidiabetic therapy; ketoacidosis
physiological regulation is
incompletely understood,
regulated by dietary composition
over days
Effective in improving glycaemic urinary and genital tract infections in
control, with added benefits of a small proportion of users
some reductions in BP and
weight
The pancreas produces insulin Hypoglycemia in combination with
more efficiently; insulin or sulphonylurea
helps control blood sugar levels. Risk of hypoglycemia
Improved gastrointestinal
tolerability, moderate plasma
drug concentration fluctuations
Increase the clearance of LDL Injection-site reactions, influenza-like
cholesterol from the circulation illness, myalgia
Increased vascular elasticity, Gastrointestinal disturbance,
improved left-ventricular- abnormalities in liver function tests,
arterial coupling, and decreased flu-like symptoms, development of
vascular permeability in diabetic antinuclear antibody, pernicious-like
rats. anemia, rare vasculitis
Activates transketolase, an Angioedema, low blood pressure
enzyme that helps apparent
AGEs,
Inhibit significant pathways
implicated in oxidative stress and
vascular dysfunction
It improves heart failure, Hypotension, disturbed kidney
decreases afterload, preload, and functions
systolic wall stress, and increases
cardiac output without
increasing heart rate
Stimulate the production of Adverse effects on cognition
soluble RAGE
(continued on next page)
M. Thakur and R.S. Tupe Prostaglandins and Other Lipid Mediators 164 (2023) 106698

Table 3 (continued )
Drug Class Associated drugs Mechanism of action Physiological actions Adverse effects References

TZDs/glitazones[181]
ALT-946b[183]
Tenilsetamb[184]
PPARγ agonists ARBs[185]
[(ex. Olmesartan, Losartan,
Valsartan, Irbesartan,
Eprosartan)]
TZDs/glitazones[186,187]
Pharmacological Aspirin[188–190]
agents/drugs for
LXs
Midazolam[191,192]
Barbiturate[193,194]
BML-111 (5(S)− 6(R)− 7-
trihydroxy-heptanoic acid
methyl ester)[195,196]
SREBP-1c inhibitors Betulin[197,198]
Clenbuterol[199]
PF-429242 (Aminopyrrolidine
amide)[200,201]
Reduces RAGE expression
Post-Amadori inhibitor by trapping
dicarbonyl intermediates, NOS
inhibitor
Post-Amadori inhibitor by trapping
dicarbonyl intermediates, NOS
inhibitor, transition metal ion chelator
Prevent the hypertensive effects of
angiotensin II by selective blockade of
the angiotensin II type 1 receptor
Antidiabetic effects through a
mechanism that involves activation of
the gamma isoform of the PPARγ
Affects the biosynthesis of lipid
mediators involved in pro-
inflammatory pathways.
Anticonvulsant activity is related to the
excess GABA action on motor circuits in
the brain. It also acts on glycine
receptors and produces a muscle-
relaxing effect.
Potentiate GABAergic inhibition by
increasing the lifetime of Cl‾ channel
opening induced by GABA
Equivalent to LXA4 in the inhibition of
inflammatory processes
Anti-inflammatory action through
glucocorticoid receptor-mediated
pathway
Upregulates CREB1 expression.
Site 1 protease inhibitor
Improved insulin sensitivity
Indicators of obesity,
cardiovascular disease, non-
alcoholic fatty liver disease
Inhibits glucose-induced
lysozyme polymerization
Vasoconstriction, simulation and
synthesis of aldosterone and
ADH, cardiac stimulation, and
renal reabsorption of sodium
Improve metabolic control in
patients with type 2 diabetes
through the improvement of
insulin sensitivity
Reduces platelet aggregation,
manages thrombotic disorders,
Inhibits cyclooxygenase and
prostaglandin formation
Anticonvulsant, anxiolytic, sleep-
inducing, muscle relaxant, and
"sedative" effects
Anticonvulsant, sedative,
hypnotic
Upregulates the mRNA and
protein expressions of PPARα,
inhibits neutrophil recruitment,
reduces the inflammatory
response
Suppresses cellular glucose
metabolism
Decreases body fat
Inhibits cholesterol and fatty acid
synthesis
fluid retention, edema, and
congestive heart failure[182]
Abnormal ALT on a long-term
outcome such as end-stage liver
disease or premature mortality
Adverse effects on patients with
severe liver and kidney diseases and
alcohol consumption.
Upper respiratory infection
Fluid retention, which can result in,
or exacerbate, edema and congestive
heart failure
Gastrointestinal bleeding, gastric
irritation,
Intravenous administration causes
respiratory and cardiovascular
depression.
Reduces neuronal activity, depress
cerebral metabolism
Negligible or no side effects, however,
transgenic mice unable to produce LX
controlled the M. tuberculosis bacteria
better with reduced mortality in
comparison to wild-type
Halitosis, orofacial pain, reduced
salivary flow, oral lesions associated
with CVDs, diabetes mellitus
Can induce cardiac hypertrophy
Hypolipidemia

Abbreviations: GLP-1, glucagon-like peptide-1; IgG1, immunoglobulin G1; BP, blood pressure; PCSK9, proprotein convertase subtilisin/kexin type 9; LDL, low-density
lipoprotein; DM, diabetes mellitus; AGE, advanced glycation end products; ACEIs, Angiotensin-converting enzyme inhibitors; ARBs, Angiotensin receptor blockers;
PPARγ, Peroxisome proliferator-activated receptor gamma; RAGE, the receptor for AGEs; HDL, high-density lipoprotein; RLP, remnant lipoprotein; TZDs, Thiazoli­
dinediones; NOS, nitric oxide synthase; ATP, adenosine triphosphate; GABA, Gamma Amino Butyric Acid; LPS, lipopolysaccharides; BMDM, Bone marrow-derived
macrophages; MSU, monosodium urate; PBMC, Peripheral Blood Mononuclear Cells; CREBP-1, Cyclic adenosine monophosphate response element binding protein
1; NADH; LXA4, lipoxin A4; mRNA, messenger ribonucleic acid, PPARα, Peroxisome proliferator-activated receptor alpha

performed on Trypanosoma cruzi, an intracellular parasite causing
devastating chronic Chagas cardiomyopathy, conveyed that inhibition
of SREBP activation improves cardiac mitochondrial stress and sup­
presses cardiac endoplasmic reticulum stress, and gradually suppresses
inflammation [156]. A study of genome scanning has associated the
17p11 region, consisting of the human SREBP-1 gene locus, with plasma
leptin concentrations and type 2 diabetes [157]. The glycoprotein78
knockout (L-gp782/2) mice are shielded from diet-/ age-induced
obesity, improving hyperlipidemia and insulin resistance. In 2012, Liu
and co-researchers generated liver-specific L-gp782/2 mice. These mice
have increased Insig-1 and Insig-2, causing SREBP inhibition [158].
Thus, gp782/2 can be inhibited to provide therapeutic direction to
alleviate metabolic diseases by inhibiting SREBP signaling.
5.2. Glycation, LXs, and SREBP signaling in contractile dysfunctions
Diabetes-induced systolic and diastolic dysfunctions affect heart
muscles, enhance muscle fibrosis, enlargement, and swelling, and design
an atherosclerotic condition and cardiac hypertrophy leading to DCM
[159]. LDL, free fatty acids, cholesterol crystals, and calcium phosphate
crystals are influx in the cells at a higher rate than their uptake in the
glycation milieu. These entities either form AGEs and activate inflam­
matory signaling pathways NF-κB through RAGE interactions or accu­
mulate on the target cells’ extracellular matrix, thereby inducing
inflammation by excess ROS formation, inflammatory cytokines release,
leukocyte activation, and their accumulation on the extracellular ma­
trix. Together, these help glycations promote lipotoxicity, and systolic
and diastolic dysfunctions in the heart through cardiac hypertrophy and
fibrosis [160], promoting DCM (Fig. 2). Glycation upregulates lipid
biogenesis by inhibiting SCAP/SREBP interaction, thereby inducing
cardiac output pressure. It becomes enlarged due to persistent hyper­
tension and undergoes pathological hypertrophy causing contractile
dysfunctions in cardiac muscles.
A study showed that metabolites generated in the arachidonic acid
pathway could mediate cholesterol homeostasis—aspirin-induced
biosynthesis of LXs-epimers reverse cholesterol transport, which is the
primary function of high-density lipoproteins. LXs mimetics also lower
plasma LDL-cholesterol, maintaining cholesterol-derived cardiac
inflammation [161]. Reverse cholesterol transport moves cholesterol
out of foam and atherosclerotic plaques to circulation, from where they
are transported to the liver and excreted in the feces [162]. This in­
dicates that LXs and mimetics relax the contractile dysfunctions in DCM
by washing off LDLs, cholesterol, inflammatory leukocytes, and platelets
from the injured site (Table 2). It is hypothesized that LXs interaction in
SREBP signaling through PPARγ receptors may help deal with cardiac
muscle systolic and diastolic dysfunctions. Glycation may enhance
contractile dysfunctions, but if, as per the hypothesis of this review,
glycation triggers biosynthesis of LXs, it may also help in the contractile

10
M. Thakur and R.S. Tupe
dysfunctions, provided this pathway is studied systematically.
6. Therapeutics in DCM
Although no particular pharmacological therapy is designed for
DCM, regulating chronic hyperglycemia, hypertension, and hyperlipid­
emia can help alleviate DCM. Most anti-diabetic drugs are proven
effective in reducing cardiovascular mortality and morbidity associated
with DCM [163]. Most cardiovascular events are treated following the
associated clinical phenotypes established in cardiology guidelines
[164,165] (Table 3). This review shows a link between glycation, LXs,
and SREBP-1c signaling via PPARγ nuclear receptors. Current treatment
strategies have multiple adverse factors associated; further studies can
target lipid metabolism therapies for DCM therapeutics in terms of
anti-diabetic drugs, AGEs inhibitors, LXs mimics, SREBP-1c inhibitors,
and PPARγ agonists.
7. Conclusion
In DCM, increased oxidative stress facilitates LDL oxidation and in­
duces lipotoxicity. Disrupted fatty acid metabolism in DCM is associated
with high SREBP-1c expression, positively regulated by PPARγ nuclear
receptors. Glycation increases lipotoxicity, while LXs upregulate PPARγ
expressions and resolve inflammation. Glycation and LXs have been
studied independently in various metabolic disorders. Furthermore,
SREBP signaling, especially SREBP-1c, is distinct in disrupting lipid
metabolism during DCM. This review suggests that the interplay of LXs
can be studied in glycation and SRBP-1c signaling pathways in
glycation-induced DCM (Fig. 6).
Different treatment comorbidities are available for DCM, as
described above (Table 3), yet, glycation-induced DCM and associated
lipotoxicity lack a specific and clear treatment line. Applying LXs in
glycation and SREBP-1c signaling can lead to a novel therapeutic
approach to treating glycation-induced DCM and lipotoxicity. As PPARγ
agonists have various adverse effects, treatment strategies can focus on
regulating its expression through AGEs/RAGE-LXs crosstalk in SREBP-1c
signaling. In summary, inhibition of the AGEs/RAGE axis, enhancement
in LXs and PPARγ activity, and adequate SREBP-1c signaling can
contribute to developing novel clinical therapies for diminishing
glycation-induced pathogenesis DCM.
Data Availability
No data was used for the research described in the article.
Acknowledgments
We thank Symbiosis International (Deemed University), Pune, for
providing the Junior Research Fellowship to Ms. Muskan Thakur (Ref:
SIU/SCRI/2021/6.4/S-06/3921).
Declaration of Competing Interest
The authors declare no conflict of interest.
Grant support
This work received no specific grant from the public, commercial, or
not-for-profit funding agencies.
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