Pflügers Archiv - European Journal of Physiology

https://doi.org/10.1007/s00424-021-02651-x

INVITED REVIEW

Understanding diabetes‑induced cardiomyopathy

from the perspective of renin angiotensin aldosterone system
Vijayakumar Sukumaran1 · Narasimman Gurusamy2 · Huseyin C. Yalcin1 · Sundararajan Venkatesh3

Received: 19 May 2021 / Revised: 2 December 2021 / Accepted: 3 December 2021

© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
Experimental and clinical evidence suggests that diabetic subjects are predisposed to a distinct cardiovascular dysfunction,
known as diabetic cardiomyopathy (DCM), which could be an autonomous disease independent of concomitant micro and
macrovascular disorders. DCM is one of the prominent causes of global morbidity and mortality and is on a rising trend
with the increase in the prevalence of diabetes mellitus (DM). DCM is characterized by an early left ventricle diastolic
dysfunction associated with the slow progression of cardiomyocyte hypertrophy leading to heart failure, which still has no
effective therapy. Although the well-known “Renin Angiotensin Aldosterone System (RAAS)” inhibition is considered a
gold-standard treatment in heart failure, its role in DCM is still unclear. At the cellular level of DCM, RAAS induces vari-
ous secondary mechanisms, adding complications to poor prognosis and treatment of DCM. This review highlights the
importance of RAAS signaling and its major secondary mechanisms involving inflammation, oxidative stress, mitochondrial
dysfunction, and autophagy, their role in establishing DCM. In addition, studies lacking in the specific area of DCM are also
highlighted. Therefore, understanding the complex role of RAAS in DCM may lead to the identification of better prognosis
and therapeutic strategies in treating DCM.

Keywords  Diabetic cardiomyopathy · Rennin angiotensin aldosterone system · Oxidative stress · Inflammation ·
Mitochondrial dysfunction · Autophagy

Introduction that directly induces abnormalities and alterations in cardiac

Cardiovascular disease (CVD) is the leading cause of death
worldwide, where diabetes mellitus (DM)–related cardiac
abnormalities increase morbidity and mortality further when
compared to CVD alone [108, 115]. DM is a chronic disease
currently affecting approximately 415 million people glob-
ally and is estimated to rise to 642 million by 2040 [64]. Dia-
betic subjects are highly prone to develop CVD due to insu-
lin resistance, hyperglycemia, and hyperlipidemia, which
play an essential pathophysiological role in developing DM
* Vijayakumar Sukumaran
vijay@qu.edu.qa; svkumar79@gmail.com
1
Biomedical Research Center, Qatar University, Al‑Tarfa,
2371 Doha, Qatar
2
Department of Bioscience Research, University of Tennessee
Health Science Center, Memphis, TN, USA
3
Department of Microbiology, Biochemistry and Molecular
Genetics, Rutgers-New Jersey Medical School, Newark, NJ,
USA
muscle and coronary function [100]. Such dysfunction leads
to impaired cardiac contractility and ventricular compliance
resulting in “diabetic cardiomyopathy” (DCM). DCM could
be developed independently of coronary artery disease and
hypertension that often accompanies DM and is induced by
a range of systemic and localized metabolic changes result-
ing in structural and functional cardiac abnormalities [49,
189]. Therefore, DCM could be an autonomous disease inde-
pendent of other cardiovascular manifestations. DCM is still
a significant challenge despite the availability of advanced
therapies to treat heart disease. The lack of knowledge in
the molecular mechanisms of the disease is one of the rea-
sons for the challenge, even though various factors are being
implicated and studied.
The well-known Framingham Heart Study showed that
DCM is one of the highest contributors to mortality among
the comorbidities that contribute to heart failure [31, 56].
DM is a strong and independent risk factor for developing
heart failure, and DCM is reported in 16–40% of type 2 DM
cases [117]. Nonetheless, type 1 DM and type 2 DM differ

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in their etiology and metabolic profiles even though both pri-
marily result in similar characteristics of DCM, which devel-
oped from a multi-factorial consequence. Many molecular
mechanisms have been proposed to contribute to the patho-
genesis of DCM, but the complex interactions between many
of the factors involved remain to be elucidated [14, 111].
The renin–angiotensin–aldosterone system (RAAS) is one
of the major signaling pathways involved in developing car-
diac abnormalities [8]. However, its role and molecular mech-
anism that contributes to the development of DCM are poorly
understood. For better prevention and strategies to improve
the treatment of DCM, it is an unmet need to understand the
molecular mechanisms and the pathophysiology of DCM.
Therefore, in this review, we focus on RAAS and its associa-
tion with various factors such as oxidative stress, inflamma-
tion, autophagy, and mitochondrial dysfunction, and how it
influences these factors in contributing to DCM development.
Pathophysiology of DCM
Unlike cardiomyopathy, the pathophysiology of DCM is com-
plicated because of multiple factors involved in its development
over time since from the initial stage of hyperglycemia. DCM
can be characterized by an initial left ventricular (LV) diastolic
dysfunction with preserved LV ejection fraction (LVEF) that
occurs significantly before changes in systolic function that are
detectable by routine assessment with echocardiography [49,
186]. This diastolic dysfunction is detectable even without LV
hypertrophy, suggesting that the LV dysfunction could be inde-
pendent of LV hypertrophy and caused by diabetes alone [3,
66, 157]. However, systolic dysfunction has also been reported
in diabetes but at a lower rate than diastolic dysfunction. Sus-
tained hyperglycemia is undoubtedly one of the main pathogenic
factors that cause structural and functional abnormalities at the
cardiomyocyte level [69]. The changes in the myocardium also
depend on the duration of diabetes. Ultimately, fibrosis at the
end may reduce the left ventricular function [62, 102]. During
the development of DCM, insulin resistance, impaired calcium
homeostasis, metabolic alterations including changes in sub-
strate utilization such as increased fatty acid oxidation, inhibi-
tion of glucose oxidation, oxidative stress, inflammation, and
the aberrant activation of RAAS signaling may directly impair
cardiomyocyte function [13, 14, 191]. Importantly, these key
contributors increase myocardial fibrosis and cellular death
resulting in cardiomyopathy followed by heart failure [13, 14].
RAAS in the development of DCM
The main effector of RAAS is angiotensin II (ANG-II).
On the other hand, renin responds to low sodium concen-
tration at the macula densa cells, not by a direct effect of
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Pflügers Archiv - European Journal of Physiology
blood pressure drop [28]. A fall in blood pressure activates
sympathetic nervous system (SNS) that indirectly releases
renin through b1 receptor stimulation in juxtaglomerular
cells. The released renin cleaves the hepatic angiotensino-
gen into angiotensin I (ANG-I), which is then converted
into ANG-II by a pulmonary angiotensin-converting
enzyme (ACE). The ANG-II restores the blood pressure
by its various physiological actions such as vasoconstric-
tion, renal sodium and water retention, stimulating the
sympathetic nervous system, and aldosterone secretion
in the adrenal glands [177]. RAAS is composed of two
opposing axes (Fig. 1). The first axis is driven by the ACE,
which produces the end product ANG-II. The A ­ T1 recep-
tor is the main effector of ANG-II, which mediates most
of its dominant biological actions. In contrast, the A ­ T2
receptor has been shown to oppose many of the activities
of the A­ T 1 receptor in the ACE/ANG-II axis [204] and
mediates at least in part some of the beneficial effects of
the ­AT1 receptor blockade on the blood vessels, heart, and
kidneys [90, 120]. Unlike A ­ T1, the role of A
­ T2 receptors
is not clearly understood. However, it is not completely
clear how diabetes affects the expression and function of
these receptors.
The second RAAS axis involves ACE-2-mediated
hydrolysis of ANG-II, leading to the production of ANG
1–7, which binds to the Mas receptor as the primary effec-
tor. This axis mediates the vasodilator, anti-inflammatory,
anti-oxidative, and anti-fibrotic actions that oppose ­AT1
receptor-mediated effects. However, the available evidence
suggests that in DM, the balance of RAAS activation is
primarily shifted towards the activation of the ACE/ANG-
II/AT1 receptor pathway [54]. Supporting evidence also
shows that hyperglycemia and DM-induced cardiac dys-
function can be reversed by pharmacological inhibition of
the ­AT1 receptor pathway [142]. Interestingly, Alaman-
dine, a newly identified heptapeptide generated by the
catalytic action of ACE-2 angiotensin A or directly from
ANG 1–7 has been identified as another element in the
protective ACE/ANG-II receptor axis [93]. Alamandine
is reported to act by binding to Mas-related G-protein-
coupled receptor (MrgD) and is potentially antagonized
by PD-123319, an A ­ T2, and MrgD antagonist but not by
the Mas receptor antagonist (A-779) [190]. However, it has
been shown that MrgD is a second receptor for ANG 1–7
[181]. But further studies are warranted to confirm these
findings and investigate how alamandine affects the struc-
ture, function of the heart, and morbidity in the long term.
Activation of RAAS elements participates in the long-
term regulation of cardiovascular homeostasis, including
modulation of cardiac contractility and coronary blood
flow via sustained activation of local ANG-II [35, 217].
Though RAAS is considered a life-saving mechanism by
regulating blood pressure during hemorrhage, RAAS also
Pflügers Archiv - European Journal of Physiology
Fig. 1  Opposing arms of RAAS involved in DCM
increases blood pressure when activated inappropriately,
leading to chronic hypertension that can contribute to the
development of cardiovascular diseases [206]. Beyond this,
various clinical trials have shown that inhibiting RAAS by
ACE inhibitors significantly reduced mortality in patients
suffering from heart failure, suggesting that RAAS could
also affect the heart apart from blood vessels [53]. Further
studies have shown that RAAS could promote ventricular
hypertrophy, fibrosis, and myocardial infarction apart from
affecting blood pressure [27, 103]. Besides, recent studies
have also shown the existence of tissue-specific RAAS,
which not only play a role in the pathophysiology of the
development of CVD but also implicated in the develop-
ment of diabetic cardiovascular abnormalities [211], where
it is involved in cardiomyocyte death, interstitial fibrosis,
hypertrophy, and atherosclerosis [19, 52, 109]. Therefore,
inhibiting the RAAS pathway by ACE inhibitors and ANG-
II receptor blockers showed a promising outcome in diabetic
cardiovascular morbidities confirming their role in DCM.
Importantly, it has been demonstrated that activating RAAS
signaling in diabetes results in tissue-specific increases in
ANG-II, the primary physiological effector molecule [96].
ANG-II contributes to numerous alterations in DCM, includ-
ing endothelial dysfunction, cardiac hypertrophy, and deple-
tion of tissue antioxidant levels, which resulted in increased
oxidative stress and vascular inflammation [45, 46]. Fur-
ther, ANG-II actions are associated with endothelial dys-
function, resulting in part from decreased nitric oxide (NO)
availability in endothelial cells [155]. Conversely, attenuat-
ing ANG-II improved endothelial function by suppressing
reactive oxygen species (ROS) production and restoring NO
availability [127]. Further, ACE inhibition has been shown
to improve mortality and morbidity in diabetic patients by
decreasing cardiovascular complications [70, 218]. The roles
of RAAS activation and the role of two axes in DCM devel-
opment are discussed further in detail.
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 Pflügers Archiv - European Journal of Physiology

ACE/ANG‑II/AT1 and ­AT2 receptor pathways
in DCM
In the classical RAAS axis, ANG-II is produced from ANG-I
by the action of ACE. ANG-II is a well-known bioactive
peptide involved in the exaggeration of cardiovascular disease
[45]. At the onset of DM and in other metabolic disorders,
activation of ACE/ANG-II/AT 1 receptor axis causes
maladaptive effects, including vasoconstriction, inflammation,
fibrosis, apoptosis, cellular growth and migration, and fluid
retention [87, 110]. ­AT1 receptors are distributed throughout
most organs, whereas ­AT2-receptor expression is observed
only in a few organs after birth and is upregulated in some
pathological states [32]. Chronic A ­ T1-receptor stimulation
is known to cause hypertension, stroke, cardiovascular
events, and renal diseases. It has also been reported that the
blockade of A­ T1 receptor promotes longevity [11]. Increased
activation of the ACE/ANG-II/AT1R pathway in rats with
enhanced tissue renin-ANG expression was observed after
6 weeks of STZ-induced diabetes. This also resulted in an
impairment of both active and passive phases of diastolic LV
function accompanied by interstitial fibrosis, cardiac myocyte
hypertrophy, and increased apoptosis along with an increase
in transforming growth factor-beta (TGF-β) activity [25]. The
modulation of ­AT1R/ERK/MAPK signaling plays a crucial
role in developing accelerated diabetes-induced cardiac
dysfunction in DCM [92]. Regimes that reduce activation of
the ACE/ANG-II/AT1 receptor pathway can slow down the
progression of DCM partially. We have previously shown that
­AT1 receptor antagonists such as olmesartan and telmisartan
attenuated apoptosis, oxidative stress, endoplasmic reticulum
stress, and cardiac inflammatory mediators and significantly
improve myocardial function [172, 173]. These findings
provide the molecular basis for the increased benefits
observed with both A ­ T1 receptor blockade (ARB) and ACE
inhibitors (ACEi) in ameliorating DCM in diabetic patients
[123, 176].
Nonetheless, although ARB and ACEi have been shown
to reduce pathological remodeling, cardiovascular events,
and mortality in diabetic patients, these conventional
therapies that target only one arm of the RAAS do not
achieve a high degree of efficacy (Table 1). In general,
cardiovascular mortality is reduced by 20–40% with either
conventional therapies, including either ARB or ACEi [30,
73, 98]. Importantly, a combination of ARB or ACEi with
the renin inhibitor Aliskiren did not improve cardiorenal
endpoints in diabetic patients with renal impairment [133].
Hence, these findings have been part of the motivation for
investigating the anti-inflammatory actions of stimulating
the non-classical arm of RAAS. In a most recent study,
it has been shown for the first time that activation of the
­AT2 receptor opposes ANG-II-mediated atherosclerosis
via ­AT1 receptor [24]. Treatment with a Compound 21, a
selective ­AT2 agonist, potently ameliorated aortic plaque
deposition in an in vivo animal model of diabetes-associ-
ated atherosclerosis through the suppression of inflamma-
tory mediators and oxidative stress [24]. Similarly, activa-
tion of AT2 also ameliorated myocardial hypertrophy in
diabetic hearts [20]. Therefore, the activation or balance
between ­AT1 and A ­ T2 receptor signaling plays an impor-
tant role in DCM development, but how the signaling is
regulated remains poorly understood.
ACE‑2/ANG 1–7/Mas receptor pathway
in DCM
The relatively recent discovery of new family members
of the RAAS system, such as ACE-2, ANG 1–7, and
ANG 1–9, has spurred new interest in understanding the
relationship between the RAAS signaling pathways and
cardiovascular disease. ACE-2, a resemblance of ACE,
catalyzes the conversion of ANG-II to a vasodilator hep-
tapeptide ANG 1–7, whereas ANG-I is converted into the

Table 1  ACE/ANG-II type 1 receptor axis modulation during the development of DCM

Organ/model Approach Effect in the heart References

Isolated cardiomyocytes AT1 antagonist ↓ NADPH oxidase, ↓ ROS production Privratsky et al. 2003 [142]
Isolated cardiomyocytes Candesartan ↓ Oxidative stress, ↓ PKC phosphorylation Yaras et al. 2007 [203]
Heart Irbesartan (IRB) ↓ Cardiac inflammation, fibrosis Westermann et al. 2007 [196]
Heart Candesartan ↓ Oxidative stress, fibrosis, myocyte apoptosis Singh et al. 2008 [164]
Isolated cardiomyocytes AT1R-KO mice, Valsartan ↓ Reactive oxygen species, cardiac apoptosis Yong et al. 2013 [208] 
Heart Valsartan ↓ Oxidative stress, cardiomyocyte apoptosis Zhang et al. 2013 [212]
Heart Valsartan ↓ Reactive oxygen species, fibrosis Thomas et al. 2013 [183]
Heart AT1R-KO mice ↓ NADPH oxidase Nagotomo et al. 2014 [121]
Eplerenone ↓ Apoptosis
Heart losartan ↓ oxidative stress and cardiac apoptosis Hussien et al. 2015 [71]
Heart Irbesartan ↓ oxidative stress and fibrosis, inflammation Watanabe et al. 2016 [193]
Heart Compound 21 + losartan ↓ oxidative stress and myocardial hypertrophy Castoldi et al. 2019 [20]

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Pflügers Archiv - European Journal of Physiology
inactive nonapeptide ANG 1–9; thereby, ACE-2 effectively
functions as an endogenous ACE inhibitor [154]. The
mechanisms underlying the beneficial actions of ACE-2
and ANG 1–7 in glucose metabolism are thought to be
multifaceted. First, increased degradation of ANG-II by
ACE-2 might be important in regulating glucose metabo-
lism [77]. Second, ANG 1–7 can activate the phosphati-
dylinositol-3-kinase–Akt pathway [40, 60, 118, 152, 182]
and thereby facilitate insulin-mediated signaling and glu-
cose uptake. ANG 1–7 might also normalize the defective
insulin signaling induced by ANG-II by preventing the
serine phosphorylation of insulin receptor substrate [143,
179], probably via inhibition of the activation of MAPK
pathways induced by ANG-II [6, 213]. Moreover, it is
now suggested that ANG 1–7 facilitates glucose uptake
by the upregulation of glucose transporter type (GLUT)
4, which is the major glucose transporter in humans [178].
Although some studies have shown that the counter-reg-
ulatory ACE2/ANG 1–7/Mas axis may promote inflam-
matory and oxidative stress responses, recent evidence
demonstrates that ANG 1–7 negatively modulates inflam-
mation, NADPH oxidase, fibrogenesis, and apoptotic
pathways in DCM [151]. In addition, it has been recently
demonstrated that ACE-2 also negatively regulates inflam-
mation, insulin resistance, and cardiac metabolism altera-
tions in obesity-mediated cardiac dysfunction [135].
Furthermore, others have reported that Irbesartan ame-
liorates LV remodeling after myocardial infarction in part
as a result of ACE-2 upregulation [84]. Chronic ANG 1–7
treatment significantly restored nitric oxide levels in the
Table 2  ACE-2/ANG-(1–7) Mas receptor axis modulation during the development of DCM
Organ/model Approach
Heart ACE-2 deletion
Heart: cardiac fibrosis ANG 1–7
Isolated perfused hearts ANG 1–7
Heart ANG 1–7
Heart ANG 1–7
Isolated cardiomyocytes ANG 1–7
Heart ANG 1–7
Heart ANG 1–7
Heart ANG 1–7
Heart ANG 1–7
Benter et al., 2007; Grobe et al., 2007; Oudit et al., 2007; Singh et al., 2011; Mori et al., 2014; Santos et al., 2014; Hao et al., 2015; Papinska et
al., 2016; Sukumaran et al., 2017
vasculature through a telomerase-dependent manner in
patients with coronary artery disease [44]. While directly
targeting the A­ T1 receptor pathway failed to improve the
outcome of cardiovascular patients [202], targeting the coun-
ter-regulatory ACE-2/Mas receptor axis by enhancing ANG
1–7 actions may yet represent a novel therapy for DCM, for
which there are limited studies (Table 2).
It is widely recognized that the increment in oxidative
stress is an important cause of disruption in cell–cell com-
munication as a consequence of ANG-II and aldosterone
formation and activation of the ACE/ANG-II/AT1 receptor
pathway [36]. Our previous study showed that ANG 1–7
elicited by the activation of ACE-2 has beneficial effects in
the heart [171], counteracting the harmful effects of elevated
ANG-II [92], and re-establishing impulse conductance dur-
ing myocardial ischemia [33]. Hence, ANG 1–7 might play
a role in maintaining functional cellular connections in the
heart by enhancing gap junction permeability with conse-
quent improvement of metabolic interactions between car-
diac cells. Recently, ANG 1–7 was also shown to increase
the gap junction permeability by activating protein kinase
A and the phosphorylation of gap junction channels [34].
Further, non-peptide ANG 1–7 receptor agonist AVE0991
has been shown to rescue hyperglycemia-induced pathologi-
cal changes in the heart [46]. Various other studies have also
pointed out the therapeutic benefits of ANG 1–7 in reduc-
ing or preventing cardiovascular abnormalities caused by
diabetes through multiple mechanisms such as reducing
lipid accumulation, systemic fat mass, inflammation, and
increased insulin-stimulation [68, 162]. Thus, the balance of
Effect in the heart References
↑ Ventricular dilation Oudit et al. 2007
↓ Intrinsic myocardial contractility [130]
↓ Hypertrophy, Interstitial fibrosis Grobe et al. 2007 [63]
↑ Vascular response to ANG-II, endothelin-1 Benter et al. 2007 [12]
↓ LV protein and collagen content Singh et al. 2011
[162]
↓ Superoxide levels, NADPH activity Mori et al. 2014 [113]
↑ Insulin sensitivity
↓ Fibrosis, inflammatory cytokines
↑ Insulin sensitivity Santos 2014 [153]
↓ Right ventricle fibrosis and apoptosis Hao et al. 2015 [68]
↓ Fibrosis, apoptosis, Superoxide levels Hao et al. 2015 [68]
↓ SERCA-2, Collagen-3, TGF-β1
↓ Fibrosis, hypertrophy and apoptosis Papinska et al. 2016
↓ Inflammatory cytokines, oxidative stress [132]
↓ Fibrosis, hypertrophy and apoptosis Sukumaran et al. 2017
[170]
13

activation between the two RAAS axes may play an essential
role in the maintenance of cellular connections in the myo-
cardium by regulating gap junction permeability between
the cardiac cells. Still, the loss of counterbalance during
the development of DCM could trigger the progression of
the disease.
RAAS and inflammation in DCM
RAAS activation appears to play a critical role in the ini-
tiation and potentiation of cardiac inflammation in DCM.
It is known that the chronic inflammation induced by pro-
inflammatory cytokines contributes to DCM development
[39, 67, 86]. Serum levels of inflammatory cytokines such
as interleukin (IL)-6, IL-1β, and tumor necrosis factor-
alpha (TNF-α) are increased in diabetic patients [41]. These
increased inflammatory cytokines cause insulin resistance by
decreasing insulin signaling due to reduced IRS-1 tyrosine
phosphorylation and the activation of PI3K and Akt [74]. In
addition, inflammatory cytokines could also directly affect
the beta cells, leading to their death and reduction in the
numbers [42]. Supporting data show that these inflammatory
cytokines are found in the hearts of diabetic patients [210].
These inflammatory mediators have been shown to promote
myocardial dysfunction leading to heart failure [197]. For
example, by overexpressing TNF-α, one of the inflamma-
tory cytokines increased cardiac fibrosis, and hypertrophy,
leading to LV dysfunction [174, 207]. Also, activation of the
pro-inflammatory transcription factor nuclear factor kappa B
(NF-κB) has been shown to trigger the generation of ROS/
reactive nitrogen species (RNS) in diabetic hearts, isolated
human cardiomyocytes, and coronary artery endothelial cells
when exposed to high glucose concentration [107, 145].
Though initially it is not clear that the inflammation is
a direct effect of RAAS activation or as a result of indirect
consequences, later studies have demonstrated that block-
ade of ANG-II signaling significantly reduces the levels of
pro-inflammatory mediators and oxidative stress in various
models of cardiac inflammation [124, 172, 173, 198]. This
is further confirmed by a recent study showing that inhibit-
ing RAAS by either Losartan or Perindopril reduced the
systemic and regional inflammatory release of monocytes
and neutrophils which resulted in the prevention of cardiac
rupture during acute myocardial infarction [58]. On the other
hand, chronic treatment with ANG 1–7 completely rescued
diastolic dysfunction in the diabetic (db/db) mouse model
by suppressing inflammation [113, 131]. These evidences
strongly supports that independent of RAAS-induced car-
diac modeling, induction of inflammatory response may
be additional factors affecting cardiac function. Moreover,
critical roles for the increased action of ANG-II and/or loss
of ANG 1–7-mediated effects have been established in a
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Pflügers Archiv - European Journal of Physiology
subsequent report in nondiabetic mice and shown that block-
ade of A­ T1 receptors by Irbesartan or infusion of ANG 1–7
exerted comparable levels of anti-inflammatory effects in
the ACE-2 null hearts of pressure-overloaded mice [134].
On the other hand, there is little direct evidence that sys-
temic inflammation markers such as c reactive protein are
frequently reported to be elevated in DM [91]. Some of the
interventions that have demonstrated protective effects are
likely to be a consequence of a reduction in cardiac inflam-
mation through various mechanisms involving ­AT1R antago-
nists and inhibition of both the MAPK pathways and inter-
leukin-converting enzyme [196, 197]. Indeed, resveratrol
has been shown to attenuate cardiac dysfunction and inflam-
mation through activation of ­AT1R/ERK/p38MAPK signal-
ing pathway in STZ-induced diabetic rats [59]. Therefore,
independent of RAAS signaling, RAAS-induced inflamma-
tion may play an additive role in DCM development. Further
studies on how RAAS induces the activation of inflamma-
tory cytokines in the heart are needed to target the RAAS-
inflammatory pathways. Therefore, it is essential to differ-
entiate between RAAS-induced and RAAS-independent
inflammation in DCM development to specifically target
the inflammation source.
RAAS and oxidative stress in DCM
Although inflammation partly contributes to cardiac remod-
eling during DCM, the presence of oxidative stress during
inflammation is inevitable, and OS is also one of the most
commonly implicated reasons in various diseases, including
DCM [85]. Oxidative stress appears to be an early contribu-
tor to the development and progress of DM, and its associ-
ated complications could be dependent or independent of
inflammation. A recent study shows that insulin resistance
leads to enhanced ROS production, inducing myocardial
oxidative stress and diminution of the antioxidant defense
mechanisms in the heart [189]. The oxidative damage caused
by ROS from a hyperglycemic state plays a vital role in dia-
betic injury in multiple cell types, including the myocardium
[65, 159, 160, 180]. In addition, ROS promotes a vicious
cycle of oxidative stress leading to changes in gene expres-
sion, faulty signal transduction, cardiomyocytes apoptosis,
and stimulation of connective tissue growth factor, fibro-
sis, and the formation of AGEs, which further exacerbate
the stiffening of diabetic hearts [106, 163]. Experimental
studies have consistently been shown that oxidative stress is
involved in vascular remodeling and diastolic dysfunction
by activating many signaling pathways, including MAPK,
calcium channels, and redox-sensitive transcription factors.
Activation of these signaling pathways causes vascular
injury through apoptosis in the vessel wall, DNA damage,
and by evoking the expression of proinflammatory genes
Pflügers Archiv - European Journal of Physiology
Fig. 2  The source of fibroblasts
in the fibrotic myocardium.
Resident cardiac fibroblasts can
be activated for its proliferation
or transdifferentiation by ANG-
II, ROS, and TGF-β. Addition-
ally, damaged cardiac myocytes,
endothelial cells, and pericytes
can be transdifferentiated into
fibroblasts or myofibroblasts
[112, 119, 185]. Notably, the elevated ROS levels and com-
promised antioxidant mechanisms are associated with dias-
tolic dysfunction and cardiac remodeling in streptozotocin
(STZ)-induced DM, as well as genetic models of type 2 DM
[72, 165, 166]. In addition, oxidative stress also appears to
be an essential driver in the pathogenesis of fibrosis in DCM
[165, 166, 184]. On the other hand, other cell types in the
heart including cardiac myoctes could be prone to transdif-
ferentiation into fibroblasts (Fig. 2). Evidence shows that
inhibition of NADPH oxidase in young rats shortly after the
onset of DM attenuates subsequent interstitial fibrosis in the
myocardium and completely prevents systolic and diastolic
function in diabetic rats [104]. The pro-inflammatory-medi-
ated ROS contribution is also evident from increased expres-
sion of TNF-α, NF-κB, and collagen in the heart of rats with
DM, which was significantly diminished by an antioxidant
N-acetyl cysteine [95, 200]. Further, hyperglycemia-induced
inflammation and fibrosis were also ameliorated by treat-
ment with an antioxidant during the development of DCM
[172], which also implies the inflammation and oxidative
stress are interconnected [166, 172].
Evidence that ANG-II promotes OS in DCM progres-
sion has also been demonstrated when insulin-like growth
factor-1(IGF-1) overexpression reduces OS and myocyte
apoptosis in the diabetic heart [80]. These are accompanied
by a reduction in nitrotyrosine, ­H2O2, and ·OH reactive oxy-
gen radicals in myocytes, probably by the decrease in the
expression of p53, Bax, angiotensinogen, ­AT1 receptors, and
ANG-II [80]. Such reduction has also been accomplished
by ­AT1 blocker losartan and the ­O2 scavenger Tiron sug-
gesting the potential role of RAAS in inducing oxidative
stress in the development of DCM [80]. On the other hand,
metallothionein, a group of small cysteine-rich metal-bind-
ing proteins, possesses antioxidant activity, and suppresses
ANG-II-dependent NOX-induced nitrosative damage and
cell death in diabetic hearts [216].
Although there is enough evidence that RAAS directly
influences OS in DCM, studies also show that RAAS might
indirectly establish oxidative stress in the myocardium dur-
ing DM. For example, hypertension that affects the diabetic
heart could be induced by an increase in the expression
of the ­AT1 receptor and ANG-II binding to ­AT1 receptor
through treatment with one of the oxidants, l-buthionine
sulfoximine (BSO), that positively correlates oxidative stress
and RAAS [9]. This is possibly by ­AT1-induced phosphoryl-
ation of Jak kinase-2, which forms a molecular complex with
calmodulin that interacts with NHE3, resulting in increased
sodium reabsorption and blood pressure. Further, treating
with antioxidant tempol or ­AT1 receptor blocker Candesar-
tan prevents oxidative stress–induced pathological changes
in ­AT1-induced hypertension, suggesting the indirect role of
RAAS-induced OS in the heart [10]. Also, additional stimu-
lation of other pathways involving NF-Kβ promotes inflam-
mation and oxidative stress resulting in the aggravation of
myocardial injury since RAAS is also shown to be localized
in many tissues, including the heart [10].
13

Established oxidative stress may further activate the
RAAS and proceed as a vicious cycle in establishing DCM.
Therefore, treating with antioxidants alone may not be effec-
tive but could be an added strategy in treating DCM. Sup-
porting experimental studies have shown that antioxidant
therapies can at least partially normalize the increased ROS
production and consequently reduce the severity of DM
[165, 166]. Notably, a high plasma glucose concentration
induces an imbalance between ROS species and NO bio-
availability as an early event in the progression of DM that
causes endothelial dysfunction [138]. Many of the antioxi-
dant treatment clinical trials have not completely rescued
the cardiovascular abnormalities [26, 146, 165, 166, 205].
Therefore, oxidative stress may not be the sole cause of
DCM but could be a mediator in DCM development. Added
antioxidant therapy may be beneficial if the source of oxida-
tive stress is correctly identified.
RAAS and its role in mitochondrial
dysfunction and contribution to DCM
Mitochondria are the central stages for metabolism and are
highly prone to diabetes-induced changes. Mitochondria
regulate most of the critical events such as ATP
production, calcium handling, β-fatty acid oxidation,
and mitophagy in the cell. Therefore, mitochondrial
dysfunction generally has var ious pathological
consequences that affect most of these key regulatory
pathways and trigger cardiac remodeling. It has been
shown that a severe reduction in mitochondrial ATP
production was observed in type 2 DM, which was
associated with cardiac abnormalities such as diastolic
dysfunction [114, 137]. Also, type 2 DM patients
undergoing coronary artery bypass surgery showed
increased oxidative stress associated with reduced
respiration in their left arterial appendage tissue [5].
In addition, change in mitochondrial energy was also
observed during impaired cardiac insulin signaling in
cardiac-specific insulin receptor deleted mice [15].
These shreds of evidence strongly suggest that cardiac
mitochondrial dysfunction has been associated with the
development of DCM independent of RAAS, including
through O-GlcNAcylation modification [16, 75, 76,
105, 144]. Although RAAS could directly induce
mitochondrial dysfunction in the heart by decreasing
mitochondrial enzyme and ETC complex activities, its
contribution to DCM through mitochondrial dysfunction
is unknown [78].
Emerging studies suggest the participation of RAAS
in mitochondrial dysfunction contributing to DCM [167,
195]. Under physiological conditions, ANG-II role in ROS
production and stimulation of redox-mediated signaling
13
Pflügers Archiv - European Journal of Physiology
are interconnected and it has been shown that in diabetes
RAAS hyperactivation is associated with ROS generation,
resulting in cell damage. RAAS and mitochondria have a
mutual role in the production of cellular ROS. While ANG-
II activates NADPH oxidase and assists eNOS uncoupling,
it also mediates mtROS generation, which further impairs
mitochondrial energy production [43, 88]. Increased expres-
sion of ANG-II via activation of ­AT1R is shown to cause
morphological and functional impairment of mitochondria
in cardiomyocytes. In addition, it has also been shown that
mineralocorticoids can activate the fibrotic effects of ­AT1R
signaling by increasing the ANG-II-induced cardiac oxida-
tive stress (Fig. 2) [175, 214].
Further evidence shows that overexpressing Ren2 chronically
activates the tissue RAAS causing mitochondrial interdigitat-
ing accompanied by hypertension, diabetes, and cardiovascular
damage [167]. However, inhibition of mineralocorticoid recep-
tors in this Ren2 transgenic mouse has been shown to rescue
mitochondrial abnormalities, suggesting that RAAS could
induce DCM phenotype possibly through mitochondrial dys-
function [167]. Another evidence suggesting that RAAS con-
tributes to mitochondrial dysfunction in the heart is that Ren2
overexpressed mice-induced aortic remodeling was rescued
by treating with mitochondrial specific antioxidant tempol,
although NADPH oxidase is shown to contribute to the majority
of ROS generation in the Ren2 transgenic mouse [195]. There-
fore, detailed studies are warranted to confirm the contribution
of RAAS-induced mitochondrial dysfunction in DCM.
RAAS and autophagy in DCM
Autophagy is a highly conserved homeostatic process that
plays an essential role in the heart to maintain normal home-
ostasis by recycling long-lived molecules, including cellular
organelles, by targeting them into lysosomes for degradation.
Therefore, autophagy could be a cardioprotective process by
reducing cellular damage to the heart against various stress
conditions [1, 122, 150, 158]. Also, autophagy can be det-
rimental, depending on the extent of autophagy and experi-
mental animal models in question. Defective autophagy is
already shown to influence skeletal and cardiac dysfunction
[55, 125]. The very first and early studies in 2009 demon-
strated that RAAS influences autophagy in cardiomyocytes,
where ANG-II increases autophagosomes in the presence of
­AT1 receptor overexpression. However, these responses were
inhibited by co-expressing a high A ­ T2/AT1 receptors ratio,
suggesting a potential reciprocal regulation of autophagy
by ­AT1 and A
­ T2 receptors [140, 141]. However, in contrast,
ANG 1–7 is negatively associated with autophagy but pro-
vides a protective function by reducing oxidative stress and
autophagy-dependent cardiac remodeling in the heart [97].
Additionally, ANG 1–7 reverses autophagic activation and
Pflügers Archiv - European Journal of Physiology
protects the heart from oxidative stress and hypertrophic
response induced by ANG-II [97]. However, the role of
autophagy in the progression or protection of DCM has
started emerging. It has been shown that during DCM, oxi-
dative stress sensitizes the heart to the activation of RAAS
signaling and induces autophagic type-II programmed cell
death, leading to accelerated cardiac remodeling and dys-
function [7, 168, 188]. Specifically, autophagy in the heart is
induced by type 1 diabetes but inhibited in type 2 diabetes,
although exact mechanisms are unclear [82]. Independent of
this, elevated oxidative stress, inflammation, apoptosis, and
ER stress induced by the increased production of monocyte
chemoattractant protein-1 (MCP-1) are suspected for contrib-
uting to the disruption of normal myocardial autophagy in
DM, which may impair the removal of damaged organelles
resulting in dysfunctional myocardium [199, 209].
On the other hand, insulin signaling itself is a
regulator of myocardial autophagy [147]. Studies show
that autophagy protein–deficient mice have diminished
autophagy and increased the production of ROS, which
activates NF-κB in infiltrating macrophages, leading to
increased cardiac inflammation and cardiac fibrosis [215].
Therefore, it can be that normal autophagy signaling
can protect the heart from hyperglycemia-induced
inflammation and cardiac injury [209]. Constitutive
autophagy is crucial during any development stage,
including the heart, to eliminate nonfunctional or
damaged cells. Therefore, a decrease in autophagy results
in abnormal protein accumulation, leading to apoptosis
and cardiac dysfunction in DCM [192, 201]. A recent
study demonstrated that timely removal of damaged
mitochondria in cardiomyocytes through autophagy
contributes to adaptive responses that result in net oxidative
stress and inflammation reductions, thus an adaptive
response that maintains homeostasis [128, 161]. As
RAAS contributes to many of the factors such as oxidative
stress, inflammation, and mitochondrial dysfunction
as described above, its role in regulating autophagy or
mitochondrial specific autophagy (mitophagy) in the
context of DCM has not been extensively studied, thus
opening a potential area of investigation. However, in
general, RAAS is shown to be positively associated with
autophagy in cardiomyocytes [23, 97]. It has also been
observed that both ANG-II and autophagy are induced
during cardiac dysfunction [140]. Altogether, and with
additional evidence, it clearly suggests that activation of
autophagy by RAAS is protective in high-glucose-treated
endothelial cells [21]. Therefore, activating autophagy
has been shown to protect cardiomyocytes by decreasing
ANG-II-induced oxidative stress and inflammation [51].
As RAAS has been shown to promote autophagy in many
cardiovascular complications such as ischemia-reperfusion
injury and cardiac hypertrophy, we believe that similarly in
DCM, we may see a protective mechanism but it requires
detailed investigation.
RAAS signaling in obesity and diet
in the development of DCM
Lifestyle modifications are one of the self-controlled hab-
its to prevent most non-genetic metabolic diseases. Poor
diet and physical inactivity are the most influential fac-
tors contributing to an increase in obesity in addition to
the multiple co-existing conditions such as hypertension,
glucose intolerance, dyslipidemia, and obstructive sleep
apnea in DCM [83]. Additionally, obesity is associated
with LV diastolic dysfunction and increases the liability of
death from cardiovascular disease, including DM, kidney
disease, and coronary heart diseases [47, 149, 187]. This
is supported by the positive clinical outcome of lifestyle
modification that has been shown to improve cardiovas-
cular function [187]. Moreover, metabolic and neurohor-
monal mechanisms have also been postulated to contribute
significantly to obesity-induced DCM. It has recently been
shown that a high-fat diet promoted progressive impair-
ment of coronary vascular function in Sprague–Dawley
rats [89]. In particular, the early stage of obesity is asso-
ciated with reduced vascular NO availability [57] and
increased production of ROS [156]. However, the patho-
physiological mechanisms linking obesity to coronary vas-
cular dysfunction remains poorly understood.
RAAS signaling in adipose tissue has been shown to
play a major role in obesity-induced cardiovascular dis-
ease [101]. It is known that ANG-II can induce mac-
rophage infiltration into the arterial walls [17, 29], and
macrophages are an essential mediator of adipose tissue
inflammation and contribute to obesity-associated meta-
bolic dysfunction [129, 194]. Inflammatory cytokines
secreted by macrophages may also impair insulin signaling
[94]. The resulting insulin resistance causes hyperglyce-
mia and increased production of AGEs and ROS, which
results in vasculature damage [38]. As stated previously,
chronic ANG 1–7 treatment completely restored diastolic
function in diabetic db/db mice by suppressing lipotoxic-
ity, adipose inflammation, and insulin resistance [61, 113].
Deletion of ACE-2 resulted in a phenotype with increased
epicardial adipose tissue inflammation, lipotoxicity, oxi-
dative stress, and cardiac dysfunction [135]. These results
suggest that ANG 1–7 and ACE-2 are negative regulators
of adipose tissue inflammation and cardiac dysfunction in
the obese state. Previous studies have also revealed that
adiponectin plays an important role in regulating glucose
and lipid metabolism [136], insulin resistance, and vascu-
lar injury [50]. Decreased adiponectin levels in the obese
subjects are associated with insulin resistance, diabetes,
13

Fig. 3  Association between
T2DM, ANG-II activation,
and the risk for cardiovascular
diseases. Insulin resistance is
induced in humans through
unhealthy life style, genetic pre-
disposition, medications, envi-
ronmental factors, and aging.
The activation of RAS increases
the oxidative stress and reduces
the NO bioavailability leading
to systemic inflammation and an
increased risk of CVD
and cardiovascular problems [79], where adiponectin
treatment could be beneficial. Adiponectin treatment
was shown to attenuate ROS-induced inflammation and
autophagy through the downregulation of AMPK/mTOR
signaling in cardiomyocytes [22, 48]. Also, adiponectin
reversed endothelial dysfunction by increasing NO produc-
tion in obese DM rats [37]. Taken together, in the context
of obesity, RAAS signaling could promote ROS and adi-
pose tissue inflammation to advance the progression from
obesity to DCM.
Interestingly, there is the interplay between the SNS
and the RAAS in obesity [81, 99], where obesity leads to
the activation of the SNS, which activates the production
of renin and angiotensinogen and consequently promotes
excessive ANG-II production. Activation of the SNS in
obese patients might partially explain the increases in LV
mass observed in obese patients as an increase in local
ANG-II production, which could stimulate hypertrophy
and fibrosis [2, 4]. Therefore, RAAS and obesity-induced
activation of the SNS in combination with DM undoubtedly
exacerbates DCM. Moreover, a recent study revealed that
the improved outcome from the exercise and diet-induced
weight loss was through the downregulation of sympathetic
nerve activity [169]. Over a 35-year follow-up period in a
Swedish cohort study, it was shown that long-term physi-
cal activity positively influences morbidity and mortality
in middle-aged participants [18]. Indeed, another study
revealed that physical activity was independently associ-
ated with a 26% reduction in the risk of DM [116]. Recent
studies also show that in both diabetic and non-diabetic con-
ditions, physical exercise increases endothelium-derived
NO production and antioxidant activation and reduces
13
Pflügers Archiv - European Journal of Physiology
oxidative stress by decreasing mitochondrial inflammation
and DNA damage induced by ROS production [126, 139].
However, an exogenous supplement of antioxidants is not
beneficial in certain conditions, especially during physical
exercise, where it could completely inhibit the activation
of the endogenous self-defense system [148]. Therefore,
understanding how obesity, physical activity, and RAAS
influence the production of ROS will be critical to manag-
ing obesity-associated DCM.
Perspectives
DCM is recognized as being highly prevalent in the diabetic
population, and risks for developing the same are higher
compared to cardiomyopathy alone. Hence, early screen-
ing and treatments are necessary to reduce the development
and progression of DCM, which further reduces the risk of
acute myocardial infarction, atherosclerosis, and heart fail-
ure. Chronic hyperglycemia and insulin resistance lead to
increased activation of RAAS signaling and vice versa that
co-exists with or without oxidative stress, inflammation,
autophagy, mitochondrial dysfunction and other co-factors,
which induce structural disturbances and functional abnor-
malities to the heart (Fig. 3). Experimental evidence support
the role of ANG 1–7 and antioxidants in reversing many of
the impairments in the myocardium, suggesting that ANG
1–7 may have a promising approach in the management of
DCM. Given that cardiovascular diseases are the principal
cause of morbidity and mortality among DM patients, the
efficacy of new therapies warrants investigation for this
growing patient population.
Pflügers Archiv - European Journal of Physiology
Acknowledgements  This study was made possible by a Rapid
Response Call (RRC) award (RRC2-076) to H. C. Y. from the
Qatar National Research Fund (a member of The Qatar Founda-
tion). Venkatesh Sundararajan’s laboratory work is partially sup-
ported by the American Heart Association grants (20CDA35260096
and 20TPA3542000)
Declarations  15. Boudina S, Bugger H, Sena S, O’Neill BT, Zaha VG, Ilkun O,
Conflict of interest  The authors declare no competing interests.
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