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1. Diabetic neuropathy and heart failure: role of neuropeptides....................................................................... 1

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Diabetic neuropathy and heart failure: role of neuropeptides


Author: Ejaz, Asma; LoGerfo, Frank W; Pradhan, Leena
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Abstract:
Cardiovascular autonomic neuropathy (CAN), in which patients present with damage of autonomic nerve fibres,
is one of the most common complications of diabetes. CAN leads to abnormalities in heart rate and vascular
dynamics, which are features of diabetic heart failure. Dysregulated neurohormonal activation, an outcome of
diabetic neuropathy, has a significant pathophysiological role in diabetes-associated cardiovascular disease.
Key players in neurohormonal activation include cardioprotective neuropeptides and their receptors, such as
substance P (SP), neuropeptide Y (NPY), calcitonin-gene-related peptide (CGRP), atrial natriuretic peptide
(ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). These neuropeptides are released
from the peripheral or autonomic nervous system and have vasoactive properties. They are further implicated in
cardiomyocyte hypertrophy, calcium homeostasis, ischaemia-induced angiogenesis, protein kinase C signalling
and the renin-angiotensin-aldosterone system. Therefore, dysregulation of the expression of neuropeptides or
activation of the neuropeptide signalling pathways can negatively affect cardiac homeostasis. Targeting
neuropeptides and their signalling pathways might thus serve as new therapeutic interventions in the treatment
of heart failure associated with diabetes. This review discusses how neuropeptide dysregulation in diabetes
might affect cardiac functions that contribute to the development of heart failure. [PUBLICATION ABSTRACT]
Full text:
(ProQuest: ... denotes non-US-ASCII text omitted.)
The prevalence of diabetes mellitus is an alarming global health issue. It is one of the six leading causes of
death in the United States, where it affects nearly 21 million people (Ref. 1). Diabetes-associated cardiovascular
complications and diabetic neuropathy have an important pathophysiological role in the progression of heart
failure in both type 1 and type 2 diabetes and account for 30% of diabetes-related complications (Ref. 2).
Cardiovascular complications associated with diabetes include coronary artery disease, peripheral vascular
disease (PVD), cardiomyopathy and heart failure. Diabetes confers a twofold increase in the risk of death from
heart failure (Ref. 3), and according to the United Kingdom Prospective Diabetes Study (UKPDS) the incidence
of heart failure correlates with the extent of hyperglycaemia: each 1% increase in haemoglobin A1C (HbA1c)
level is associated with a 12% increase in heart failure risk (Ref. 4).
Diabetic neuropathy is a cluster of different neuropathies that vary in symptoms, pattern of neurological
involvement and underlying mechanisms (Ref. 5). It is a common complication, affecting 60-70% of patients
(Ref. 5). For almost a century, since the term 'diabetic neuropathy' was proposed, scientists have been
investigating not only the causes of diabetic neuropathy, but also the consequences of this common
complication. The first report on the presence of sugar in urine dates back to 1674; however, the neurological
symptoms associated with diabetes were first reported almost 200 years later in 1864 by De Calvi, and the first
clinical study implicating diabetes in the degeneration of peripheral nerves was conducted in 1929 (Ref. 6).
Neurohormonal activation has a strong pathophysiological role in diabetes, insulin resistance and
cardiovascular disease. However, the role of neurohormones and their neuropeptide effectors in diabetesassociated heart failure is not fully understood. In diabetes, the levels of both autonomic and sensory
neuropeptides are dysregulated in the myocardium (Ref. 7). These cardioactive neuropeptides include
neuropeptide Y (NPY) (Ref. 8), substance P (SP; also known as tachykinin 1 or TAC1) (Ref. 9), calcitonin-generelated peptide (CGRP; also known as CALCA/B) (Ref. 10) and the natriuretic peptides (NPs), atrial natriuretic
peptide (ANP; also known as A-type natriuretic peptide), brain natriuretic peptide (BNP; also known as B-type
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natriuretic peptide) and C-type natriuretic peptide (CNP) (Ref. 11). In addition to these neuropeptides, their
receptors are also affected in diabetes, and thereby the downstream neuropeptide signalling cascade is
disrupted.
Our hypothesis therefore is that the diabetic milieu causes neuropathy, leading to severe dysregulation of
neuropeptide expression or activation within the myocardium. This impairment in neuropeptide signalling
contributes to the cardiac dysfunction and heart failure associated with diabetes. The major goal of this review is
to provide up-to-date information on the role of neuropeptides in diabetic heart failure. In doing so, we begin
with a broad overview of the mechanisms of diabetic heart failure and diabetic neuropathy and end with an indepth analysis of the different neuropeptides that might be affected in diabetes and that have a role in the
cardiovascular system.
Mechanisms of diabetic heart failure
Diabetes and associated complications such as hypertension, dyslipidaemia, obesity, inflammation, poor
glycaemic control, autonomic neuropathy, coronary artery disease or diabetic cardiomyopathy are all linked to
heart failure (Ref. 3). Autonomic neuropathy that is independent of vascular disease is also involved in major
cardiovascular events such as myocardial infarction, ischaemia, fibrillation, or angina and heart failure (Ref. 12).
As illustrated in Figure 1, diabetes causes autonomic neuropathy, and vascular and cardiac dysfunction.
Autonomic neuropathy, in turn, can cause neuropeptide dysregulation. This dysregulation further contributes to
vascular diseases and cardiac dysfunction, ultimately leading to cardiovascular dysfunction and heart failure
(Fig. 1). The dysregulation in neuropeptides might be a major nodal point connecting diabetes and autonomic
neuropathy to heart failure.
Figure 1
Mechanisms of diabetic heart failure. Diabetes is known to lead to autonomic neuropathy, vascular disease and
cardiac dysfunction. Autonomic neuropathy can lead to neuropeptide dysregulation. Diabetes-associated
vascular diseases include peripheral vascular disease (PVD), hypertension and atherosclerosis. Diabetesassociated cardiac dysfunctions include left ventricular (LV) dysfunction and cardiomyopathy. Neuropeptide
dysregulation might further contribute to cardiovascular dysfunction that can finally lead to heart failure.
Vascular diseases are major causes of physical disabilities and death in patients with diabetes (Ref. 13), and
account for approximately 80% of all deaths among diabetic patients (Ref. 14). Diabetes increases the risk for
development of coronary atherosclerosis (Ref. 15), which in turn significantly enhances the risk of heart failure
(Ref. 16). Additionally, coronary artery disease is the primary cause of heart failure in approximately two-thirds
of patients with left ventricular (LV) systolic dysfunction (Ref. 17). The pathophysiology of vascular disease in
diabetes includes abnormalities in the function of endothelial cells, vascular smooth muscle cells (Ref. 18) and
platelets, and a change in haemostatic factors (Ref. 19). Hyperglycaemia, increased free fatty acids and insulin
resistance all contribute to vascular dysfunction (Ref. 20).
Diabetic cardiomyopathy, defined as a myocardial dysfunction, is a distinct primary disease that is independent
of coronary artery disease and predisposes to the progression of heart failure (Ref. 16). Risk factors for diabetic
cardiomyopathy are age, hypertension, obesity, coronary artery disease and hyperlipidaemia, and it is
characterised by LV hypertrophy, and diastolic and systolic dysfunction (Ref. 21). Metabolic abnormalities might
also have an important role in the progression of myocardial dysfunction, which leads to hyperglycaemia,
impaired myocardial glucose uptake, increased free fatty acids and insulin resistance. These factors result in
biochemical events leading to cardiomyopathy and heart failure (Ref. 22).
Diabetic neuropathy
Diabetic neuropathies are heterogeneous and involve dysfunction of large myelinated fibres and small thinly
myelinated or nonmyelinated fibres. Small-fibre neuropathy results in a reduction of nerve growth factors and
other neurotransmitters such as SP and CGRP (Ref. 23). The pathogenesis of diabetic neuropathy is probably a
combination of metabolic and neurovascular factors that lead to a decreased supply of oxygen and nutrients to
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nerves in diabetic patients (Ref. 24). These patients can develop neuropathy at any stage, but risk progresses
with age, inadequate glycaemic control and duration of diabetes (Ref. 25). Diabetic neuropathy can be classified
as peripheral, autonomic, proximal and focal, each of which affects different parts of the body in different ways.
Peripheral neuropathy, also called distal symmetrical neuropathy or sensory motor neuropathy, is most
common, and affects the nerves of the extremities (Ref. 26). Autonomic neuropathy most often involves the
nerves that control the heart, regulate blood pressure and control blood glucose levels (Ref. 27). Focal
neuropathy affects the nerves in the head, torso and legs. Proximal neuropathy is generally caused by
inflammation, affects the lower limbs, and is characterised by a variable degree of pain and sensory loss
associated with unilateral or bilateral proximal muscle weakness and atrophy (Refs 28, 29).
Several pathogenic processes might be involved in diabetic neuropathy, including glycosylation, metabolic insult
to nerve fibres, autoimmune destruction, deficiency of the neurovascular, neurohormonal growth factors and
oxidative stress (Fig. 2) (Ref. 30). Hyperglycaemia leads to activation of the polyol pathway, leading to
activation of protein kinase C (PKC), which induces vasoconstriction and neuronal damage and reduces
neuronal blood flow (Ref. 31). Hyperglycaemia-induced oxidative stress causes vascular endothelial damage
and reduces nitric oxide (NO) bioavailability (Ref. 32), whereas excess NO results in nitrosative stress and
damage to the endothelium and neurons (Ref. 33). Autoimmunity and inflammation are also involved in
neuronal loss and dysfunction (Ref. 30). Reduction in neurotrophic factors, deficiency of essential fatty acids
and formation of advanced glycation end products (AGEs) result in reduced endoneurial blood flow and nerve
hypoxia with altered nerve function (Ref. 34).
Figure 2
From diabetic neuropathy to heart failure. Diabetes results in activation of the polyol pathways, formation of
advanced glycation end products (AGEs), oxidative stress and immune dysfunction. These factors lead to
autonomic neuropathy. Diabetes is known to cause vascular and cardiac dysfunction. Autonomic neuropathy
can lead to neurohormonal dysregulation, which disrupts neuropeptide function. Neuropeptide dysregulation,
either directly or perhaps by dysregulated neuroinflammation, contributes to vascular and cardiac dysfunction by
modulating vascular tone, impairing angiogenesis, causing cardiomyopathy and left ventricular (LV)
hypertrophy, and affecting systolic and diastolic functions. These cardiovascular dysfunctions can ultimately
lead to heart failure.
Diabetic autonomic neuropathy
Diabetic autonomic neuropathy is a serious complication resulting from long-term diabetes that has a negative
impact on survival and quality of life (Ref. 35). Diabetic autonomic neuropathy involves the entire autonomic
nervous system, including the gastrointestinal, genitourinary and cardiovascular systems (Ref. 36). The signs,
symptoms and treatment of diabetic autonomic neuropathy vary, depending on the cause and the nerves that
are affected. Clinical signs and symptoms include resting tachycardia, exercise intolerance, orthostatic
hypotension, silent myocardial ischaemia, erectile dysfunction, impaired neurovascular function, 'brittle diabetes'
and hypoglycaemic autonomic failure (Ref. 36).
Cardiovascular autonomic neuropathy
Cardiovascular autonomic neuropathy is the most investigated form of diabetic autonomic neuropathy (Ref. 36).
In cardiovascular autonomic neuropathy, nerve fibres that innervate the heart and blood vessels are damaged,
resulting in abnormalities in the heart and vasculature (Ref. 37). Diabetic patients with this form of neuropathy
have a five times higher cardiac mortality than diabetic individuals with other forms of neuropathy (Ref. 38). The
incidence of cardiovascular autonomic neuropathy is 16.8% for type 1 diabetes and 22.1% for type 2 diabetes
(Ref. 39). The increased mortality might be a result of the direct effect of autonomic neuropathy itself and the
indirect effect of accelerating microvascular complications (Ref. 38). Cardiovascular autonomic neuropathy
results in both parasympathetic and sympathetic dysfunction, resulting in increased resting heart rate. The
combined parasympathetic and sympathetic dysfunctions might be followed by a fixed heart rate (Ref. 40) as
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detected by loss of heart rate variability (Ref. 41). The Action to Control Cardiovascular Risk in Diabetes
(ACCORD) trial showed that cardiac autonomic neuropathy is associated with high mortality (Ref. 42).
Cardiovascular autonomic neuropathy and left ventricular dysfunction
Coronary artery disease and hypertension are associated with LV dysfunction (Ref. 43). Cardiovascular
autonomic neuropathy, through alteration in myocardial blood flow and sympathetic denervation, and changes
in myocardial neurotransmitters of the neuropeptidergic system (such as SP, CGRP, vasoactive intestinal
peptide and NPY) can cause LV dysfunction (Ref. 43). Cardiovascular autonomic neuropathy correlates with LV
diastolic dysfunction (Ref. 44) in type 2 diabetes, and is associated with LV hypertrophy or higher LV mass
index, and diastolic and systolic dysfunction in type 1 diabetes (Ref. 45). Other studies in cultured rat myocytes
(Ref. 46) and canines (Ref. 47) have shown that hypertrophy or higher LV mass index might be due to
sympathetic stimulation or prolonged infusion of norepinephrine.
Cardiovascular autonomic neuropathy and neuropeptides
There is increasing evidence that reduction or loss of neural activation is associated with cardiovascular
autonomic neuropathy in diabetes (Ref. 48). The level of pancreatic polypeptide and NPY is absent or low in
type 1 diabetic patients with cardiovascular autonomic neuropathy than in individuals without it (Ref. 8). It has
been shown that the level of NPY in diabetic patients might be a useful marker of sympathetic nerve failure
(Ref. 49). The expression of autonomic neuropeptides such as NPY and vasoactive intestinal peptide is
significantly reduced in cardiovascular autonomic neuropathy patients with rheumatic diseases (Ref. 50).
Moreover, acrylamide-induced autonomic neuropathy of rat mesenteric vessels shows the greatest reduction in
intensity and number of CGRP and SP nerves (Ref. 51). Reduced expression of SP and CGRP is also
observed in cardiovascular autonomic neuropathy patients (Ref. 23).
Diabetes, heart and neuropeptides
NPY, SP, CGRP, ANP, BNP and CNP are vasomodulators released from the central and peripheral nervous
systems (PNS). These neuropeptides have an important role in cardiomyocyte hypertrophy (Refs 52, 53),
ischaemic revascularisation (Refs 54, 55), wound healing (Refs 56, 57), myocardial contractility (Refs 58, 59),
PKC activation (Ref. 60), modulation of the rennin-angiotensin-aldosterone system (RAAS) and AGEs (Ref. 61).
These neuropeptides affect several important functions that maintain cardiovascular homeostasis; therefore,
any changes in their signalling can lead to cardiovascular dysfunctions.
Neuropeptide Y
NPY is a 36-amino-acid peptide. It is one of the most abundantly and ubiquitously distributed neurotransmitters
in the central nervous system (CNS) and the PNS (Ref. 62). In the CNS, NPY is mainly released from the
paraventricular nucleus of the hypothalamus (Ref. 63) and appears in the cerebrospinal fluid (Ref. 64). NPY is
also produced by vascular smooth muscle cells, endothelial cells, vas deferens cells and pancreatic acinar cells
(Refs 63, 65). It signals through G-protein-coupled receptors with six subtypes: NPY1R, NPY2R, NPY3R,
NPY4R, NPY5R and NPY6R (Ref. 66). NPY and its receptors NPY1R, NPY2R and NPY5R have an important
role in the pathophysiology of a number of diseases, including diabetes, heart failure, hypertension, PAD and
feeding disorders (Ref. 67). Furthermore, these receptors are involved in angiogenesis (Ref. 55), calcium
homeostasis (Ref. 67), RAAS and PKC activation of diabetes and heart failure (Ref. 68). NPY stimulates the
growth of vascular smooth muscle cells (Ref. 69) and also has a critical role in atherosclerosis and stressrelated alterations of immunity (Ref. 65).
NPY and diabetes
NPY levels are decreased in patients with type 1 diabetes with cardiac autonomic neuropathy (Ref. 8). NPY
expression is also reduced in the heart, hippocampus and frontal cortex tissue of streptozotocin (STZ)-induced
diabetic rats (Ref. 70). Conversely, in the arcuate nucleus of rats, insulin and hypoglycaemia increase the
transcription of the gene encoding NPY (Ref. 71).
NPY, when acting through its receptor NPY1R, causes vasoconstriction. In alloxan-induced diabetic rabbits, the
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contractile effect of NPY is reduced in cerebral and coronary vessels (Ref. 72). Clinically, vascular smooth
muscle contractile response to NPY is markedly attenuated in diabetic patients (Refs 73, 74). Thus, in diabetes,
it is not just the expression, but also the effect of exogenous NPY, that is diminished in the vasculature.
In contrast to the above studies, in a recent study, plasma NPY levels were increased in patients with type 2
diabetes (Ref. 75). As mentioned earlier, non-neuronal cells such as smooth muscle cells, endothelial cells,
pancreatic acinar cells and vas deferens cells can produce NPY. In patients with chronic type 2 diabetes, a
compensatory increase in these extraneuronal sources of NPY might explain the discrepancy.
NPY and the heart
NPY is located in the sympathetic nerve endings of the coronary vasculature and cardiac myocytes of humans
and many other species. Functional NPY receptors in the heart are NPY1R, NPY2R and NPY5R (Ref. 67). In
rats, NPY is co-stored and co-released with norepinephrine and ATP in the postsympathetic nerve terminal and
with epinephrine in the adrenal medulla (Ref. 76). However, at presynaptic nerve terminals, NPY inhibits the
release of norepinephrine by a negative-feedback mechanism (Ref. 76). NPY, acting through NPY1R and
NPY5R, has a pathogenic role by inducing cardiac hypertrophy and vasoconstriction of coronary vessels (Refs
65, 77). In rat models, NPY leads to vasoconstriction indirectly by potentiating the effect of norepinephrineinduced calcium signalling (Ref. 78) and by a direct effect of NPY on increasing intracellular calcium ([Ca 2+]i)
(Ref. 79). NPY induces angiogenesis through NPY2R and NPY5R, and thus has an imperative role in ischaemic
revascularisation and wound healing (Refs 52, 56). Therefore, in diabetic patients with reduced NPY expression
or activity, there could be a diminished angiogenic response after ischaemia or after wounding, seriously
affecting recovery.
Although plasma NPY levels have also been shown to be increased in diabetic patients, there is a decrease in
neuronal NPY expression in the right atrium of diabetic patients undergoing coronary artery bypass surgery
(Ref. 75). The same study showed that NPY2R and NPY5R expression is increased within the diabetic right
atrium. This increase in receptor expression could be counter-regulatory to the reduced NPY expression in the
myocardium. In a rat model of long-term type 1 diabetes, similar results are observed, with a reduced
expression of NPY and an increased expression of NPY1R in the myocardium of diabetic rats (Ref. 80).
Although NPY is a vasoconstrictor in most vascular beds, in the myocardium it decreases contractility. In
isolated perfused rat myocardium, NPY decreases the positive chronotropic effect of phenylephrine and
isoprotrerenol by decreasing the activity of sarcolemmal Na +/K+ ATPase (Ref. 81). In a similar rat model, NPY
decreases the positive inotropic effects induced by agonists without having a direct effect (Ref. 59).
NPY also stimulates protein synthesis in adult rat cardiomyocytes by activation of pertussis toxin-sensitive Gproteins and phosphoinositol 3-kinase, and induces the fetal-type creatinine kinase-BB by activation of PKC and
mitogen-activated protein kinase (Ref. 82). Exposure of mouse neonatal cardiomyocytes to NPY induces rapid
phosphorylation of the extracellular responsive kinase the Jun N-terminal kinase and the p38 kinase, as well as
activation of PKC (Ref. 83).
In a swine model of chronic myocardial ischaemia, exogenous addition of NPY increases mean arterial pressure
and improves LV function without changing blood flow (Ref. 84). However, there is an increase in capillary and
arteriole formation, along with upregulation of NPY1R, NPY2R, NPY5R, vascular endothelial growth factor
(VEGF), endothelial nitric oxide synthase (eNOS), phospho-eNOS (p-eNOS) on Ser1177 and platelet-derived
growth factor (PDGF), and downregulation of antiangiogenic factors endostatin and angiostatin in the NPYtreated group (Ref. 84). This large animal study emphasises the role of NPY in ischaemic angiogenesis wherein
all the important angiogenic (pro- and anti-) factors are affected by NPY. However, the study does not address
the connection or lack thereof between increased ischaemic myocardial angiogenesis, with unchanged blood
flow achieved by NPY treatment. In addition to its effects on angiogenesis and myocardial function, NPY also
activates diuretic and natriuretic properties in vivo (Refs 52, 85, 86) and promotes the clearance of water and
electrolytes by increasing the release of ANP from isolated rat left atrium (Ref. 87). NPY has a prominent role in
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the kidneys, as demonstrated in an isolated rat kidney study, where it induces renal vasoconstriction and
inhibits renin release by inhibiting adenylate cyclase activity in vascular smooth muscle and renin-producing
cells (Ref. 61). In a rat myocardial infarction model of moderate compensated congestive heart failure,
continuous infusion with NPY led to a decrease in renin levels (Ref. 88).
Thus, NPY and its receptors have a diverse role in the cardiovascular system by affecting almost all
components of this system; therefore, any perturbations in its expression or signalling can have serious effects.
There does not seem to be a single common pathway that it evokes. However, its role as a proangiogenic
molecule seems to be the most consistent of its cardiovascular effects, with serious implications in diabetesassociated heart failure and the reparative response to a myocardial infarction. Its role in cardiac hypertrophy
and vasoconstriction, although not clearly understood, can serve as a contributory factor towards development
of diabetic heart failure.
Substance P
SP is an undecapeptide that functions as a neurotransmitter and a neuromodulator that alters the excitability of
the dorsal horn ganglion (pain-responsive neurons) (Ref. 89). It is expressed in the CNS and the PNS (Ref. 90)
and is released from sensory nerve fibres. Enteroendocrine cells are one of the major sources of endocrine and
circulating SP (Ref. 91). SP is involved in several physiological activities, including maintenance of
cardiovascular tone, smooth muscle activity, vomiting reflex, defensive behaviour and stimulation of salivary
secretion (Ref. 92). The SP receptor, also known as neurokinin 1 receptor (NK1R), belongs to the tachykinin
receptor subfamily of GPCRs. NK1R is present in a variety of cell types, including immune cells, epithelial cells,
endothelial cells, glial cells and neurons. The interaction of SP with NK1R activates Gq, which in turn activates
phospholipase C with the net rise in [Ca2+]i that induces tissue response (Ref. 93). SP is metabolised by the
enzyme enkephalinase, a zinc metalloprotease that is also known as neutral endopeptidase (NEP) and is
present in the cell membrane of cells that express NK1R (Ref. 94).
SP and diabetes
SP expression is decreased in the CNS and PNS of patients with type 1 and type 2 diabetes (Ref. 9). In the
nonobese type 1 diabetic mouse model, administration of SP impedes chronic, progressive -cell stress,
reduces islet cell inflammation, reduces insulin resistance and restores normoglycaemia (Ref. 95). Similarly,
skin biopsies from both type 1 and type 2 diabetes patients show a reduced density of SP nerve fibres (Ref. 96).
In type 2 diabetic patients, decreased expression of neuronal NOS and SP is accompanied by a deficiency of
gastric interstitial cells of Cajal associated with diabetic gastroparesis (Ref. 97). NK1R is the predominant
receptor through which SP is known to exert its effect, and signalling through this receptor is affected in most
diseases whenever SP is implicated. However, there are a few studies suggesting a change in NK1R
expression itself. In one study, a decrease in NK1R expression was observed in the dorsal root ganglia of
diabetic rats (Ref. 98). These studies suggest that, unlike NPY whose expression could be up- or
downregulated in diabetes, SP expression is always downregulated. This downregulation is the effect of
diabetes and hyperglycaemia that might lead to sensory denervation and neuropathy.
SP and the heart
Although not an autonomic neuropeptide, SP is significantly associated with cardiovascular regulation (Ref. 99).
Most of its effects counteract the effect of autonomic effectors such as norepinephrine and epinephrine. In
addition to enteroendocrine cells, other major sources of circulating SP are perivascular nerves. SP release
through perivascular nerves contributes to the regulation of vascular tone and acts as a vasodilator, in addition
to reducing the effect of vasoconstrictive factors in patients with congestive heart failure (Ref. 100). Our lab has
recently shown that SP increases human dermal microvascular endothelial cell proliferation and tube formation,
but the exact mechanism is not clear (Ref. 57). Also, SP expression is reduced in cutaneous wounds of diabetic
rabbits (Ref. 101). Several reports have shown that SP enhances the release of NO, which preserves the
expression of sarcoplasmic reticular Ca 2+ ATPase by opposing norepinephrine. This effect of SP protects
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myocardial calcium homeostasis and heart function (Refs 99, 102). A recent canine study shows that atrial
fibrillation leads to ventricular remodelling with a decrease in SP-positive nerves (Ref. 103). Also, blockade of
NK1R deteriorates postischaemic recovery of heart in a mouse model (Ref. 104). Furthermore, increasing
expression of SP protects the heart from injury by enhancing NK1R expression in guinea pigs and rats (Ref.
105). Another recent rat study shows that loss of cardioprotection by ischaemic postconditioning during diabetes
is partly associated with failure to increase the release of CGRP and SP in diabetic hearts. This study also
shows that SP and CGRP induce ischaemic postconditioning in both nondiabetic and diabetic hearts,
preventing ischaemia-reperfusion injury by improving cardiac function as a consequence of lower levels of
creatinine kinase and cardiac troponin I (Ref. 106). Treatment with SP reverses LV hypertrophy in patients with
essential hypertension (Ref. 107). Plasma levels of SP are increased in heart failure patients receiving ACE
inhibitors compared with those given a placebo, suggesting that ACE breaks down SP (Ref. 108). Thus, ACE
inhibitors, in addition to their effect on blocking the expression of angiotensin II, can increase the expression of
SP and therefore add to their therapeutic effects. In contrast to the above studies, which show cardioprotective
effects of SP, there are fewer studies implicating SP in the pathophysiology of cardiomyopathy and heart failure.
Whether the increase in SP is a cause or effect of the underlying pathology is not clear from these studies. In a
randomised, double-blind, placebo-controlled study using the NK1R antagonist aprepitant, SP causes a tonic
enhancement of sympathetic outflow to some cardiovascular structures by modulating NK1R (Ref. 109).
In another study of acute myocardial infarction, within 15min of coronary artery occlusion, there was an
increase in SP in the rat myocardium (Ref. 110). Moreover, this study also showed that SP regulates cardiac
function through NK1R by modulating adrenergic actions through the protein kinase A pathway (Ref. 110). In a
rodent model, SP induced parasitic dilated cardiomyopathy (Ref. 111) and, similarly, SP was increased in
patients with moderate and severe congestive heart failure (Ref. 112).
Because of its vasodilatory and angiogenic effects, SP seems to have a cardioprotective role that can be
compromised in diabetes where SP expression is diminished. In cardiovascular diseases where SP is
implicated, its increased expression might be a counter-regulatory effect to negate the effect of sympathetic
effectors. In diabetes, where such compensation by SP cannot be achieved as a result of the lack of SP-positive
nerves, therapies should be designed for supplementation with SP. Therefore, to determine the 'cause' or
'consequence' role of SP, additional studies are warranted to perform a more in-depth analysis of this molecule
in animal models of diabetes-associated cardiac dysfunction.
Calcitonin-gene-related peptide
CGRP is a 37-amino-acid peptide synthesised in the CNS and the PNS, which is generated from the alternate
splicing of mRNA encoding calcitonin in a tissue-specific manner (Ref. 10). CGRP normally colocalises with SP
in the sensory nervous system and is a potent vasodilator; it also has various biological effects and both
circulatory and neurotransmitter modes of action (Ref. 113). The effects of CGRP are mediated by the activation
of at least two CGRP receptor subtypes: CGRP1R and CGRP2R (Ref. 114). In addition, calcitonin-receptor-like
receptor has also been described as a CGRP receptor (Ref. 115) that always requires receptor-activitymodifying protein 1 (RAMP1) (Ref. 116).
CGRP and diabetes
CGRP shows about 50% homology with amylin, colocalises with insulin (Ref. 117) and somatostatin (Ref. 118)
in the islets of Langerhans, and might be involved in the synthesis or release of insulin from secretory granules
(Ref. 117). It is a circulating hormone that modulates peripheral insulin sensitivity (Ref. 119). Studies have also
shown that CGRP has trophic effects on the pancreas, myotubules, motor neurons and peripheral nerves (Ref.
10). In rodent models, CGRP ameliorates -cell destruction and reduces the occurrence of type 1 diabetes (Ref.
120). The number of CGRP-immunoreactive cells was significantly decreased in a rat model of type 1 diabetes
(Ref. 105). CGRP levels are also lowered in the serum of STZ-induced hyperglycaemic rodents (Ref. 98).
Impaired CGRP expression has also been shown in the hearts of diabetic STZ mice (Ref. 121).
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CGRP and the heart


CGRP is found in the human heart, where it exerts complex cardiovascular effects including a protective effect
against heart failure by curtailing the workload of the heart (Ref. 122). CGRP supports the heart by inducing
potent vasorelaxation by the release of NO and cyclic guanosine monophosphate (cGMP) (Ref. 119), which
protects myocytes and endothelial cells from damage (Ref. 123), and modulating the immune system to reduce
inflammation (Ref. 124). In rats, the cardiovascular protection of nitroglycerin is partly modulated by the release
of endogenous CGRP (Ref. 125). In a recent rat cardiac ischaemia-reperfusion study, pretreatment with CGRP
improved cardiac contractility and overall outcome (Ref. 126). Similarly, as mentioned earlier in a rat study, SPand CGRP-induced postconditioning significantly prevented both nondiabetic and diabetic hearts from
ischaemia-reperfusion injury. Ischaemic postconditioning markedly increased CGRP and SP release in
nondiabetic hearts, but failed to affect CGRP and SP release in diabetic hearts, indicating that the loss of
cardioprotection by ischaemic postconditioning during diabetes is partly associated with failure to release CGRP
and SP (Refs 106, 127). Clinical studies show that, in addition to cardiac effects, CGRP increases angiogenesis
by increasing VEGF-A, basic FGF (bFGF) and transforming growth factor- (TGF-) in a hind-limb ischaemia
model (Ref. 128). Thus, CGRP not only improves cardiac function, but can also facilitate recovery
postischaemia by increasing capillary formation and cardiac blood flow.
These studies show that in the heart and vasculature, CGRP is similar to SP in expression and activity and can
affect the cardiovascular system in a positive manner. Therefore, in diabetes, where CGRP is found to be
decreased, the effects on the cardiovascular system and, more specifically, recovery post-ischaemia can be
significantly hampered. There are fewer studies of CGRP in diabetes models compared with studies on SP;
however, similarities in the effects of CGRP and SP suggests that CGRP supplementation could prove to be
beneficial in the treatment of cardiovascular dysfunction of diabetes.
Natriuretic peptides
NPs are comprised of three structurally related molecules: ANP, BNP and CNP (Ref. 129). NPs have three
discrete receptors, A-type natriuretic receptor (NPRA), B-type natriuretic receptor (NPRB) and C-type natriuretic
receptor (NPRC) (Ref. 130). ANP and BNP are cardiac peptides, released from atrial and ventricular myocytes,
and bind to NPRA and NPRB, whereas expression of CNP is limited to the CNS and it selectively binds NPRC
(Ref. 131). Moreover, these receptors are homodimeric and catalytic and have guanylyl activity on the
intracellular domain of the protein sequence (Ref. 132). NPRA and NPRB are linked to guanylyl cyclases,
leading to the production of cGMP, which in turn leads to relaxation of smooth muscle cells and cardiomyocytes
(Ref. 133). NPRAC is a GPCR that removes NPs from the circulation and is often termed a 'clearance' receptor
(Ref. 129). These peptides have potent natriuretic, diuretic and vasodilating activities, and regulate vessel size,
ventricular hypertrophy, pulmonary hypertension, fat metabolism, fluid egress, increased glomerular filtration,
and salt and water excretion (Ref. 134). NPs impede the action of angiotensin-converting enzyme (ACE),
angiotensin II, NEP, aldosterone and vasopressin (Refs 135, 136).
NPs and diabetes
NPs have antioxidant activity that inhibits oxidative stress and ameliorates the endothelial dysfunction of
diabetes in a rat model (Ref. 137). In several studies, dysfunction of natriuretic peptide receptors has been
observed in STZ diabetic rats (Refs 11, 138, 139, 140). Impairment of NPRA uncoupling is involved in diabetic
heart failure (Ref. 141), and the expression of NPRA receptors is reduced in diabetic rat kidneys (Ref. 139).
BNP has been shown to be a reliable predictor of patients with type 2 diabetes and is a potential marker of
diastolic heart failure (Ref. 142). Heart failure patients with diabetes have elevated BNP levels compared with
patients without diabetes (Ref. 143). In a recent study, the gene encoding NPRC was found to have different
single-nucleotide polymorphisms in diabetic patients, one of which significantly correlated with increased
systolic blood pressure in this population (Ref. 144).
These studies indicate that not only NPs, but also their receptors, are significantly affected in diabetes. Although
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related, ANP and BNP have very distinct profiles and yet both are good predictive tools in diabetic heart failure
patients.
NPs and the heart
NPs have a vital role in congestive heart failure (Ref. 111). Natriuretic peptide receptors (NPRs) are located on
the endocardial endothelium and might be involved in regulating myocardial contractility (Ref. 58). It has also
been shown that NPs reduce myocardial load and enhance systolic and diastolic function in normal hearts and
in failing hearts of canines (Ref. 145). ANP exerts cardioprotective functions, not only as a circulating hormone,
but also as a local autocrine or paracrine factor as shown in an in vitro study of endothelial and vascular smooth
muscle cells (Ref. 146). In vitro models demonstrate that it has antihypertrophic and antifibrotic functions and
that it inhibits apoptosis and proliferation (Ref. 147). These results are corroborated in a mouse model that lacks
NPRA and hence develops cardiac hypertrophy and fibrosis (Ref. 148). Moreover, ANP attenuates RAAS,
sympathetic nerve activity and reperfusion injury, averts LV remodelling and improves LV function in patients
with acute myocardial infarction (Ref. 149). In addition to inhibiting RAAS, ANP also inhibits NEP, the enzyme
that breaks down SP (Ref. 135). Thus ANP can indirectly increase the levels of SP. Omapatrilat, a
pharmacological dual inhibitor of NEP and ACE, is a promising agent for the treatment of hypertension, heart
failure and renal failure, as demonstrated in a rat study (Ref. 150). This suggests that ANP, which is an
endogenous dual inhibitor, might have the same beneficial effects. In canines, blockade of ANP accelerates the
progression of heart failure and postmyocardial infarction (Refs 151, 152).
In patients, plasma BNP is an important prognostic marker for the outcome of acute congestive heart failure and
is a biomarker for myocardial ischaemia (Refs 153, 154). The level of BNP is generally higher in patients with
worse outcomes (Ref. 155). Moreover, the plasma concentration of BNP is also typically increased in patients
with asymptomatic or symptomatic LV dysfunction (Ref. 155). In contrast to these studies, short-term
administration of subcutaneous BNP during the evolution of LV dysfunction in a canine model resulted in
considerable improvement in cardiovascular haemodynamics (Ref. 156).
Therefore, similarly to NPY, it is not clear whether low or high levels of ANP and BNP are desired for
cardioprotection. In diabetes, there is decreased expression and activity of ANP, and thereby a loss of
cardioprotection; therefore, supplementing exogenous ANP might be cardioprotective. In most studies of
diabetes and cardiovascular disease, there is increased expression and activity of BNP. However, because of
contradictory results, it is not clear whether inhibition or supplementation of BNP will have a positive effect on
the cardiovascular system. Therefore, more in vivo studies need to be performed to analyse the role of BNP in
diabetes and associated cardiovascular dysfunctions.
Summary
These studies show that the role of neuropeptides in diabetic heart failure is not established and the results are
sometimes disparate. Table 1 summarises what we currently understand about the role of neuropeptides in
diabetes and the cardiovascular system. Among the neuropeptides, NPY has received the most attention in
both diabetes and cardiovascular diseases. Yet, it is not clear whether NPY has an protective or pathological
role in cardiac dysfunction. The sensory neuropeptide SP has an undisputed protective role in the
cardiovascular system, and in diabetes it is known to be consistently downregulated. Therefore, it could serve
as a key therapeutic target in the treatment of diabetic heart failure. CGRP, similarly to SP, might have a
cardioprotective role and would therefore also serve as a good therapeutic target in the treatment of diabetesassociated heart failure. However, studies investigating the role of CGRP in diabetes-associated cardiovascular
dysfunction are few, and hence the role of CGRP needs more analysis. NPs also have very important roles in
the cardiovascular system, but their role in diabetes remains unclear. ANP has been shown to be
cardioprotective, but the role of BNP is not fully understood. Thus, BNP also warrants deeper scrutiny.
Table 1
Role of neuropeptides and their receptors in diabetes and the cardiovascular system
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Abbreviations: ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CGRP, calcitonin-gene-related
peptide; CHF, chronic heart failure; CNP, C-type natriuretic peptide; LV, left ventricular; NPs, natriuretic
peptides; NPRA, A-type natriuretic receptor; NPY, neuropeptide Y; RAAS, renin-angiotensin-aldosterone
system; SP, substance P.
The role of neuropeptides in other diabetic complications, such as wound healing, has been examined much
more aggressively. Scientists investigating diabetic heart failure might find neuropeptide wound-healing studies
useful for designing cardiovascular research models. In wound-healing studies, neuropeptides have been
shown to affect the immune system by regulating immune cell trafficking and cytokine signalling (Ref. 57).
Perhaps neuropeptides can similarly regulate neuroinflammation in the cardiovascular system and, more
importantly, in the myocardium. Therefore, we hypothesise that neuropeptide dysregulation is the common
mechanism underlying wound healing and cardiovascular dysfunction in diabetes. Diabetes causes activation of
polyol pathways, generation of AGEs and oxidative stress, and a dysfunctional immune response. All these
factors contribute to the development of autonomic neuropathy. Diabetes also causes vascular and cardiac
disease, sometimes independently. It is our hypothesis that diabetic neuropathy causes neurohormonal
dysfunction, leading to dysregulation of neuropeptides and neuroinflammation. Neuropeptide dysregulation,
either directly or perhaps by dysregulated neuroinflammation, contributes to vascular and cardiac dysfunction by
modulating vascular tone, impairing angiogenesis, causing cardiomyopathy and LV hypertrophy, and affecting
systolic and diastolic functions. Finally, these cardiovascular dysfunctions can lead to heart failure (Fig. 2).
Conclusion
Diabetic heart failure is a significant and debilitating health problem that has a negative impact on both quality of
life and survival. A review of existing literature suggests that diabetic neuropathy can lead to neuropeptide
dysregulation and thereby has very important role in the pathophysiology of heart failure. Reducing the
incidence of cardiac autonomic neuropathy or modulating neuropeptide and receptor function in diabetes
directly might curtail cardiac dysfunction and heart failure. Understanding the complexity of neuropeptide
function is a step towards identifying a therapeutic plan. For these reasons, further studies are warranted to
delineate more precisely the role and signalling mechanisms of neuropeptides in diabetic heart failure.
Acknowledgements and funding
We thank the peer reviewers for their constructive criticism, time and effort. This work was funded in part by the
William J. von Liebig Foundation.
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Further reading, resources and contacts
S. Tesfaye (2010) Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and
treatments. Diabetes Care 33, 2285-2293
A.I. Vinik and T. Erbas (2006) Cardiovascular autonomic neuropathy: diagnosis and management. Current
Diabeties Reports 6, 424-430
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These two reviews provide detailed and up-to-date information on diabetic neuropathy.
V. Baliga and R. Sapsford (2009) Review article: Diabetes mellitus and heart failure-an overview of
epidemiology and management. Diabetes and Vascular Disease Research 6, 164-171
A good source of information on diabetes-associated heart failure.
L. Pradhan (2009) Inflammation and neuropeptides: the connection in diabetic wound healing. Expert Reviews
in Molecular Medicine 11, e2
This review explores the relationship between neuropeptides and neuroinflammation in diabetic wound healing.
AuthorAffiliation
Department of Surgery, Division of Vascular and Endovascular Surgery, Beth Israel Deaconess Medical Center,
Harvard Medical School, Boston, MA, USA
Subject: Diabetes; Studies; Heart failure; Cardiovascular disease; Peptides;
MeSH: Animals, Humans, Diabetic Neuropathies -- physiopathology (major), Heart Failure -- physiopathology
(major), Neuropeptides -- physiology (major)
Substance: Neuropeptides;
Publication title: Expert Reviews in Molecular Medicine
Volume: 13
Pages: e26
Number of pages: 19
Publication year: 2011
Publication date: Aug 2011
Year: 2011
Publisher: Cambridge University Press
Place of publication: Cambridge
Publication subject: Medical Sciences--Internal Medicine
Source type: Scholarly Journals
Language of publication: English
Document type: Feature, Journal Article
DOI: http://dx.doi.org/10.1017/S1462399411001979
Accession number: 21831336
ProQuest document ID: 882301383
Document URL: http://search.proquest.com/docview/882301383?accountid=31223
Copyright: Copyright Cambridge University Press 2011
Last updated: 2015-08-15
Database: Medical Database

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