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Gumede, N.A.; Khathi, A. Role of POMC Derivatives in Cardiovascular Function. Encyclopedia. Available online: (accessed on 16 April 2024).
Gumede NA, Khathi A. Role of POMC Derivatives in Cardiovascular Function. Encyclopedia. Available at: Accessed April 16, 2024.
Gumede, Nompumelelo Anna-Cletta, Andile Khathi. "Role of POMC Derivatives in Cardiovascular Function" Encyclopedia, (accessed April 16, 2024).
Gumede, N.A., & Khathi, A. (2024, February 16). Role of POMC Derivatives in Cardiovascular Function. In Encyclopedia.
Gumede, Nompumelelo Anna-Cletta and Andile Khathi. "Role of POMC Derivatives in Cardiovascular Function." Encyclopedia. Web. 16 February, 2024.
Role of POMC Derivatives in Cardiovascular Function

Myocardial infarction (MI) is a significant contributor to CVD-related mortality. Type 2 diabetes mellitus (T2DM) is a risk factor for MI. Stress activates the hypothalamus–pituitary–adrenal axis (HPA axis), sympathetic nervous system (SNS), and endogenous OPS. These pro-opiomelanocortin (POMC) derivatives increase the blood glucose and cardiovascular response by inhibiting the PI3K/AkT insulin signaling pathway and increasing cardiac contraction. Sustained activation of the POMC derivatives may lead to developing myocardial infarction. Suffering from T2DM and stress increases the risk of developing CVD. T2DM is preceded by prediabetes, which is a state of blood glucose level being above normal but below the level of T2DM diagnosis. Research has shown that T2DM-related complications begin during prediabetes; therefore, there is a possibility of the dysregulation of the POMC derivatives during prediabetes and pathways that could lead to myocardial infarction.

pro-opiomelanocortin catecholamines glucocorticoids opioids type 2 diabetes prediabetes myocardial infarction

1. Introduction

Myocardial infarction (MI) is the sudden death of myocardial tissue due to hypoxia and ischemia following a blockage of a coronary vessel. The coronary vessel is often blocked by an atherosclerotic or thrombotic plug growth or rupture [1]. Ischemia starves the cardiomyocytes of nutrients and causes metabolic and iconic imbalances in the cells and, ultimately, death [2]. Despite the numerous interventions to reduce the mortality of CVD, it is still the most significant contributor to global mortality [3]. In 2019, 32.9% of the global 15.6 million deaths were due to CVD [4]. According to the Global Disease Burden, in 2019, ischemic heart diseases (IHDs) accounted for 197.2 million prevalent cases and 9.1 million deaths [5]. The contributing risk factors to IHD include hypertension, low-density lipoprotein cholesterol (LDL-C), diabetes mellitus, and smoking [6]. These risk factors are also prevalent in type 2 diabetes mellitus (T2DM) [7]. Psychosocial stress as a risk factor for CVD is often overlooked, yet in observational studies, chronic work stress is associated with a 40–60% increase in the occurrence of coronary heart diseases [8]. In patients with MI and unstable angina, a history of economic stress and social isolation significantly increased the risk of cardiovascular events [9]. The hyperactivity of the hypothalamus–pituitary–adrenal axis (HPA axis), sympathetic nervous system (SNS), and increased inflammation are some of the mechanisms that are postulated to link psychosocial stress and the development of MI [10]. Β-endorphin is simultaneously released with adrenocorticotropic hormone (ACTH) from pro-opiomelanocortin (POMC) when the HPA axis response is activated by stress and is involved in attenuating acute stress responses [11]. Chronic stress increases the risk of developing T2DM, CVD, and mental health disorders [12]. The HPA axis and the SNS are hyperactivated in T2DM and have been linked with the development of CVD [13][14]. Studies have reported that T2DM-related disorders begin during prediabetes, which is a condition that precedes T2DM [15]. Prediabetes is an asymptomatic state in which the blood glucose levels are above normal but below the threshold of T2DM diagnosis [16]. Prediabetic individuals with severe perceived stress are reported to have high HbA1c levels [17]. This indicates that stressed prediabetic individuals are at a high risk of progressing to T2DM and its complications [18]. Prediabetes is reported to be an independent risk factor for MI and increases the likelihood of experiencing MI by 25% [19].

2. POMC Derivative Signaling

2.1. Glucocorticoids

Glucocorticoids (GCs), such as cortisol in humans and corticosterone (CORT) in rodents, are cholesterol-derived hormones secreted by the zona fasciculata of the adrenal glands [20]. Glucocorticoids are fundamental in maintaining resting and stress-related homeostasis [21]. Animals respond to stress by activating various behavioral and physiological responses collectively called the stress response [22]. As summarized in Figure 1, the principal effectors of the stress response are localized in the paraventricular nucleus (PVN) of the hypothalamus, the anterior lobe of the pituitary gland, and the adrenal gland. This structure collection is commonly called the hypothalamic–pituitary–adrenocortical (HPA) axis. In response to stress, corticotropin-releasing hormone (CRH) is released into hypophysial portal vessels that access the anterior pituitary gland. The binding of CRH to its receptor on pituitary corticotropes induces the release of adrenocorticotropic hormone (ACTH) into the systemic circulation. The adrenal cortex is the principal target for circulating ACTH, which stimulates glucocorticoid synthesis and secretion from the zona fasciculata [22]. The cellular availability of GCs is determined by two enzymes that have opposing effects: 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) oxidizes cortisol into the inactive metabolite cortisone, whereas 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) converts cortisone to cortisol. Therefore, in normal physiology, GC levels are tightly regulated by a negative feedback loop at the level of the hypothalamus and pituitary gland, the availability of CBG in circulation, and at target tissues through the action of 11βHSD1 and 11βHSD2 [23].
Figure 1. Activation of the hypothalamic–pituitary–adrenocortical axis and glucocorticoid activation and regulation. HPA axis, hypothalamic–pituitary–adrenocortical axis; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; 11β-HSD1, 11-beta-hydroxysteroid dehydrogenase type 1; 11β-HSD2, 11-beta-hydroxysteroid dehydrogenase type 2; GR, glucocorticoid receptor; HSP, heat shock protein; GRE, glucocorticoid response element; NF-κB, nuclear factor kappa B [24].
Both endogenous and pharmacological GCs act through a dual system formed of corticosteroid receptors: the GC receptor (GR/NR3C1) and the mineralocorticoid receptor (MR/NR3C2) [25]. Upon activation through the binding of GC, GR undergoes a conformational change and dissociates from accessory proteins such as heat shock proteins (HSP-90, p60/Hop, HSP-70) and migrates to the nucleus, where the GC/GR complex binds to a promoter region called the glucocorticoid response element (GRE), causing an increase or decrease in transcription [26][27]. GCs also have a non-genomic action in which they do not bind to GR but rather to transmembrane receptors and activate mitogen-activated protein kinases (MAPKs), adenylyl cyclase (AC), protein kinase C (PKC), and heterotrimeric guanosine triphosphate-binding proteins (G proteins) [27][28]. The redox state during oxidative stress drives cardiomyocyte and vascular smooth muscle cell MR activation by GCs [29]. The functions of GC can be summed up as follows: Firstly, it prepares the metabolic, autonomic, psychological, hemostatic, and cardiovascular components of the stress response. This involves other stress hormones such as catecholamines, glucagon, and angiotensin II (ANGII) through the stimulation of alpha and beta-adrenergic receptors and the ANGII receptor. Secondly, it prevents inflammation, cellular proliferation, and the tissue repair process from over-activation, leading to injury. Thirdly, it prepares the body for prolonged nutrient deprivation by facilitating muscle proteolysis [30]. Though GCs are essential for maintaining homeostasis, excessive or impaired glucocorticoid secretion can adversely affect the body [31]. Increased GC levels due to chronic stress, exogenous therapy, or endocrine disorders commonly lead to atherosclerosis hypertension and increase the risk of developing cardiomyopathies [32].

2.2. Catecholamine

Catecholamines are a group of molecules that act as neurotransmitters and hormones in the sympathetic division of the autonomic nervous system [33]. Catecholamines and glucocorticoids are the principal hormones secreted in response to extrinsic or intrinsic stressors to maintain homeostasis [34]. Catecholamines are produced from tyrosine hydroxylation to DOPA (l-3,4-dihydroxyphenylalanine) and a series of cellular reactions that ultimately produce dopamine (D), norepinephrine (NE), and epinephrine (E) from the adrenal medulla [35]. The SNS and adrenal medulla release epinephrine. It is involved in several physiological functions, including regulating blood pressure, vasoconstriction, cardiac stimulation, and blood glucose levels [36]. Norepinephrine is mainly produced by neurons within the locus coeruleus (LC) and takes part in diverse motor and mental functions, including locomotion control, motivation, attention, cognition, and memory formation [37]. Catecholamines rapidly respond to stress by binding to adrenergic receptors at the threatened site and the alerted brain, heart, and muscles [34][35][38]. Adrenoceptors (ARs) are categorized into alpha (α1 and α2) and beta (β1, β2 and β3) receptors. Norepinephrine activates α-AR and β1-AR, while epinephrine activates all subtypes of α- and β-AR [39]. The α1-AR receptors bind to stimulatory Gq proteins, activate phospholipase C (PLC), and induce constriction. On the contrary, α2-AR receptors are coupled to G inhibitory (Gi) proteins that inactivate adenylyl cyclase (AC), decreasing cyclic adenosine monophosphate (cAMP) production [40]. Β1-AR predominates in the heart and binds to the G stimulatory (Gs) protein–AC–cAMP–protein kinase A (PKA) signaling cascade, which results in the phosphorylation of troponin I, the L-type Ca2+ channel, phospholamban (PLN), and the cardiac ryanodine receptor (RyR), thus resulting in increased cardiac contraction and relaxation [41]. Β2-AR is distributed extensively throughout the body but is expressed predominantly in bronchial smooth muscle cells [39].
The stimulation of β2-AR activates the Gi protein, which inhibits cAMP and activates mitogen-activated protein kinase (MAPK) and cytosolic phospholipase A2 (cPLA2), thus resulting in cAMP-independent Ca2+ enhancement and reduced cardiac contraction [41]. β3-ARs are abundantly expressed in white and brown adipose tissue, increasing fat oxidation, energy expenditure, and insulin-mediated glucose uptake [39]. Β3-AR is stimulated by catecholamines only at high doses and has negative inotropy (decreased contraction) by facilitating the nitric oxide synthase (NOS) pathway. Nebivolol is reported to restore hemodynamic properties in patients with heart failure by stimulating β3-AR [42]. Figure 2 illustrates catecholamine adrenergic signaling.
Figure 2. Catecholamine adrenergic signaling. Catecholamines are released from the adrenal medulla and SNS and bind to the G-protein coupled alpha- and beta-adrenergic receptors. SNS, sympathetic nervous system; B1AR, beta-1-adrenergic receptor; B2AR, beta-2-adrenergic receptor; A1AR, alpha-1-adrenergic receptor; A2AR, alpha-2-adrenergic receptor; AC, adenylyl cyclase; Gs, stimulatory G-protein subunit; Gi, inhibitory G-protein subunit; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; PLN, phospholamban; SERCA, sarcoplasmic endoplasmic reticulum calcium ATPase; RyR2, ryanodine receptor 2; DHPR, dihydropyridine receptor; Ca2+, calcium; PI3K, phosphoinositide-3-kinase; PDK1, phosphoinositide-dependent kinase 1; AkT, protein kinase B; RAS, Ras protein; RAF, Raf protein; MAPK, mitogen-activated protein kinase; PLC, phospholipase C; PIP2, phosphatidylinositol biphosphate; IP3, inositol triphosphate; DAG, diacylglycerol; PKC, protein kinase C; PP1, protein phosphatase 1; cTnT, cardiac troponin T; cTnI, cardiac troponin I; ↓, indicates activation; ┴ indicates inhibition; yellow circle indicates phosphorylation.

2.3. Opioids

The endogenous opioid peptides consist of endorphins, dynorphins (DYNs), and enkephalins (ENKs) [43][44]. There are four types of endorphins: alpha (α), beta (β), gamma (γ), and sigma (σ) endorphins. β-endorphins are primarily synthesized and stored in the anterior pituitary gland from their precursor protein, pro-opiomelanocortin (POMC) [43]. Dynorphin (DYN) is derived from a precursor protein, prodynorphin. Prodynorphin is cleaved to yield dynorphin-B, which has two extended forms (dynorphin-A and dynorphin-B), and leumorphin. In the peripheral circulation, dynorphin-A and dynorphin-B are further cleaved to yield dynorphin A (1–13) (DYN-A(1–13)), dynorphin A (1–8) (DYN-A (1–8)), and dynorphin B (1–13) (DYN-B (1–13)) and rimorphin, respectively [45]. Enkephalins are derived from the precursor protein proenkephalin (PENK) and interact with glutamate and dopamine in the brain reward circuit [46]. Endogenous opioids activate the mu (µ) (MOR), kappa (κ) (KOR), and delta (δ) (DOR) opioid receptors [43][44]. Opioid receptors signal through G-protein coupled receptors by stimulating inhibitory G-proteins, thus causing the Gαi subunit to dissociate from the Gβγ subunit and inhibit cAMP production. The Gαi subunit also interacts with the G-protein gated inwardly rectifying potassium channel (Kir3), thus causing hyperpolarization. The Gβγ modulates Ca2+ conduction by reducing the activation of N-type, P/Q-type, and L-type Ca2+ channels [47]. Signaling through the Gαi/o coupled proteins causes negative inotropy in rats’ ventricular myocytes by inhibiting cAMP-dependent Ca2+ [44]. The activation of KOR activates Gαi/o proteins, inhibiting the AC production of cAMP and releasing Gβγ, which modulates the conduction of Ca2+ and K+ channels [48]. Dynorphin provides cellular protection through the Gαs/cAMP/PKA signaling pathway, which causes an increase in CREB phosphorylation to enhance cell proliferation [49]. The distribution of OPR throughout the limbic system is consistent with the role of endogenous opioids in attenuating stress [50]. The stress system activates the dopaminergic reward system and the amygdala, thus forming a positive feedback loop [51]. The CRH stimulates the hypothalamus to release an α-melanocyte-stimulating hormone (α-MSH) and β-endorphin from the POMC-containing neurons in the arcuate nucleus. The α-MSH and β-endorphin inhibit CRH and the LC/NE system, thus regulating the stress response [51].
The naturally occurring δ-opioid peptide agonist, leucine enkephalin (LE), is co-released with the β-AR agonist norepinephrine (NE) from the nerve terminals in the heart during sympathetic stimulation. LE inhibits NE-induced increases in sarcolemma L-type Ca2+ current, cytosolic Ca2+ transient, and contraction [52]. The “anti-stress” activity of endogenous opioids may be mediated explicitly by the MOR [50]. During acute stress, the MOR regulation of the LC opposes the excitatory effect of CRH and protects against the detrimental NE/E hyperactivity effects. These opposing functions promote recovery after stress termination [53]. Mice with selective deletion of β-endorphin, enkephalin, or dynorphin subjected to the zero-maze test show increased anxiety-related behavioral responses [54]. Corticosterone plasma levels rapidly increased in all strains and returned to baseline after 60 minutes in b-endorphin-deficient mice [54].
In contrast, mice lacking dynorphin and enkephalin showed longer-lasting elevated corticosterone levels, which delayed the stress reaction termination [54]. Overall, upon release, opioids oppose the effect of glucocorticoids and catecholamines by inhibiting Ca2+ and Na+ channels while activating K+ channels. Figure 3 illustrates cardiac opioid signaling.
Figure 3. Cardiac opioid signaling. Upon release, opioids bind to G-protein-coupled opioid receptors and regulate cardiac contraction. Ca2+, calcium; Na+, sodium; K+, potassium; AC, adenylyl cyclase; Gαi/o, G protein inhibitory unit; TRPV1, transient receptor potential cation channel subfamily V member 1; cAMP, cyclic adenosine monophosphate; ATP, adenosine triphosphate; PKA, protein kinase A; RAS, Ras protein; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositol-3-kinase; AkT, protein kinase B. ↓ indicates activation; ┴ indicates inhibition; ↓ (red arrow) indicates a decrease.

3. Role of POMC Derivatives in Cardiovascular Function

3.1. Glucocorticoids

Glucocorticoids are essential for the embryonic development of the heart and the maintenance of normal myocardial function. Adrenalectomized rats with GC insufficiency have a reduction in contractile force generation by the heart papillary muscle [55]. Dexamethasone (DEX), an exogenous GC, increases contractility tension and accelerates contraction velocity and relaxation in cardiac muscle [56]. The hearts of GR-null and smooth muscle-specific knockout (KO) mice exhibit irregularly shaped and disorganized myofibrils at the embryonic stage. Furthermore, the expression of genes that are critical for cardiac development and function is diminished in the heart [57]. GC protects from atherosclerosis and inflammation [58]. Mice lacking endothelial GR develop severe atherosclerotic lesions in the aorta and have heightened inflammation in the lesions [59].
High-dose corticosteroids are reported to exert cardiovascular protection through the non-genomic activation of eNOS. The binding of CORT to the GR stimulates PI3K and Akt, leading to eNOS activation and NO-dependent vasorelaxation. Furthermore, acute administration of pharmacological CORT concentrations in mice leads to decreased vascular inflammation and reduced myocardial infarct size following ischemia and reperfusion injury [60]. Overall, GCs are needed for the structural development of the heart and protect the heart from inflammation and atherosclerosis.

3.2. Catecholamines

The activation of the SNS results in the release of catecholamines, which increase the supply of energy and oxygen delivery [61]. In fight-or-flight mode, NE/E stimulates glycogenolysis, gluconeogenesis, and aerobic glycolysis, inhibiting glycogen synthesis to supply glucose to vital organs [62]. Epinephrine increases blood glucose by stimulating glucagon secretion from mouse α-pancreatic cells through the activation of the α1 and β-AR on the α-pancreatic cell [63]. Glucagon, in turn, stimulates ACTH-induced cortisol release [64]. The stimulation of β-AR in adipocytes activates lipolysis through the activation of adenylyl cyclase and a cascade of reactions, which leads to the phosphorylation of hormone-sensitive lipase (HPL) and adipose triglyceride lipase (ATGL) [65]. It has been reported that catecholamine-induced lipolysis inhibits glucose uptake by inhibiting the PI3K–Akt–mTOR pathway [66]. Plasma concentrations of cortisol and E are significantly elevated in infants with severe hypoglycemia [67]. These mechanisms provide an acute increase in glucose levels.
The spread of electrical impulses from cardiac autorhythmic cells stimulates the myocardium to contract, thus enabling the heart to pump blood to the blood vessels [68]. The electrical impulses are initiated by the sinoatrial (SA) node and result in atrial depolarization and atrial contraction; the impulse is then conducted to the internodal pathway, the AV node, the AV bundle, the left and right branches of the bundle of His, and lastly, the Purkinje fibers, which result in ventricular depolarization and contraction [68]. The activation of β1-AR increases the SA node’s firing rate, which, in turn, increases contractility because of an increased Ca2+ release from the sarcoplasmic reticulum and conduction through the AV node. The stimulation of α1-AR stimulates vasoconstriction and increases peripheral resistance [69]. The net effect is increased BP and cardiac output (CO) due to enhanced cardiac excitation, impulse conduction, and cardiac contraction [70]. Overall, catecholamines increase blood glucose by inhibiting glucose uptake while stimulating glucose release and synthesis. Catecholamines also increase blood pressure by increasing the firing rate of the SA node, Ca2+ concentration, and vasoconstriction.

3.3. Opioids

The cardiovascular regulatory effects of endogenous opioids were initially considered to originate from the central nervous system. However, opioid peptides of myocardial origin have been shown to play essential roles in the local regulation of the heart [71]. A portion of POMC mRNA that contains a sequence for β-endorphin is expressed in the cardiac muscle, thus indicating that β-endorphin is produced in the heart [72]. Cell culture experiments from neonatal rat hearts revealed that myocytes and non-myocytes express ppENK mRNA [73]. Β-endorphin (1–31) is the primary endorphin form present in the cardiac muscle, although substantial amounts of N-acetylated and des-acetyl p-endorphin-(1–27) and P-endorphin-(1–26) are also detectable [74]. The cardiac tissue of rats subjected to immobilization stress has elevated β-endorphin [75]. Cardiac MOR expression is elevated in chronic heart failure and plays a cardioprotective role by reducing infarct size, the phosphorylation of ERK, and glycogen synthase-3-β (GSK3β) [76]. Infusions of high-dose β-endorphin in hypertensive subjects are reported to cause a decrease in systemic vascular resistance, blood pressure, plasma NE, and endothelin-1(ET-1) and raise atrial natriuretic factor P (ANP), thus protecting the heart [77]. The stimulation of OPR not only inhibits cardiac excitation–contraction coupling but protects the heart against hypoxic and ischemic injury [71]. Myocardial methionine-enkephalin levels increase with the severity of hypoxic stress in congenital cardiac disease. They may play an essential adaptive role in countering adrenergic over-activity and related excess demand on myocardial metabolic capacity [78]. Dynorphin provides cardiac protection during hypertension. Intracerebroventricular injections of β-endorphin and dynorphin A (1–13) in anesthetized rats result in hypotension and bradycardia [79]. Dynorphin A (1–13) also modulates epinephrine-induced cardiac arrhythmias by increasing the threshold for or suppressing the manifestation of the induced cardiac arrhythmias [80]. Receptor-dependent and independent stimulation of the adrenergic signaling pathway is reported to cause an increase in ppENK mRNA and modulate the dromotropic response to catecholamine stimulation in rat myocardial cells [73]. In stress-induced cardiac injury, the activation of central MOR with endogenous opioids is reported to aggravate stress-induced cardiomyopathy, while the stimulation of peripheral µ-opioid receptors produces a cardioprotective effect [81]. Overall, opioids counteract the effects of catecholamines on the heart. Opioid receptors are elevated during hypoxia and cardiac ischemic injury and attenuate the extent of cardiac damage. Figure 4 summarizes the cardiovascular function of POMC derivates.
Figure 4. Summary of the cardiovascular function of POMC derivates. Glucocorticoids play a role in cardiogenesis, stimulate cardiac contractility and vasodilation, are anti-inflammatory, and inhibit atherosclerosis. Catecholamines cause an increase in the release of calcium, excitation–contraction coupling and contractility, peripheral resistance, and blood pressure. Opioids oppose the functions of catecholamines. eNOS, endothelial nitric oxide synthase; Ca2+, calcium; ET-1, endothelin 1; BP, blood pressure; HR, heart rate; CO, cardiac output. ↑ indicates an increase; ┴ indicates a decrease.


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