G-Proteins in Cardiovascular Diseases: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Nikhlesh Singh.

G-proteins are a family of specialized proteins that can bind to nucleotides, i.e., guanosine triphosphate (GTP) and guanosine diphosphate (GDP); thus, they are also known as guanine nucleotide-binding proteins. G-proteins are either composed of a single subunit (monomeric) or multiple subunits (heterotrimeric). G-proteins and their receptors are extensively expressed in the cardiovascular system and are involved in the pathophysiology of cardiovascular diseases. Much of the G-protein signaling is mediated by several signaling effectors, such as adenylyl cyclase (AC), Ras homology (Rho), cell division cycle 42 (cdc42), phospholipase C (PLC), and SRC, which contribute to various diverse cellular processes.

  • G-proteins
  • G-protein-coupled receptors
  • signaling
  • cardiovascular diseases

1. Heart Failure

Heart failure (HF) is a medical condition that develops when the heart cannot pump enough blood to meet the body’s needs. HF affects over 6.5 million American adults and results in an annual healthcare burden of USD 30 billion [2][1]. Heart failure (HF) is a common and serious condition with substantial morbidity and mortality rates. HF is associated with structural or functional abnormalities caused by cardiomyocyte enlargement and hypertrophic growth. Several intrinsic and extrinsic stimuli, such as stress, cytokines, and growth factors, are sensed by cardiomyocyte receptors such as GPCRs, causing detrimental effects [17][2]. Inotropic and chronotropic hyporesponsiveness to adrenergic stimulation, as well as a decrease in Gs-alpha proteins, or an increase in Gi-alpha proteins, lead to congestive heart failure [67][3]. In these conditions, there is strong sympathetic activation, which causes a decrease in beta-adrenergic activity. In terms of membrane receptors, beta1 receptors are downregulated, and beta2 receptors are uncoupled. Even without beta-adrenergic receptor downregulation, an increase in Gi proteins can suppress adenylate cyclase activity. These results demonstrate that the Gi protein desensitization of adenylate cyclase can serve as an essential pathophysiological mechanism in the development of compensated cardiac hypertrophy to HF, because cardiac hypertrophy is a major predictor of HF [68][4]. Additionally, similar changes can be observed with aging [69][5].
Acetylcholine-dependent activation of cardiac potassium channels regulates heart rate. G-protein beta signaling mediates the activated muscarinic receptor-induced stimulation of cardiac potassium channels. The G-protein-coupled inwardly rectifying potassium channels (GIRKs) encode cardiac potassium channels. GIRK1 and GIRK4 are two members of the GIRK family located in the heart [70,71][6][7]. The cell membrane becomes hyperpolarized due to an interaction between the activated G-protein subunits (G) released by GPCRs and GIRK channels for potassium ion permeability. The neuron cannot fire action potentials quickly when it is hyperpolarized, which slows the heartbeat [72][8]. It is also emphasized that SUMOylation, O-GlcNAcylation, acetylation, and phosphorylation all play a role in the pathogenesis of HF and cardiac remodeling [73][9].
GPCRs are essential in numerous physiological processes and therefore are targets of pharmaceutical therapeutics. For instance, the activation of β-adrenergic receptors (βARs) and Ang II type 1 receptors (AT1Rs) results in myocyte death and adverse cardiac remodeling, as well as an increased heart workload [74][10]. To transmit signals, AT1Rs couple to Gαq, Gβγ, and β-arrestin and form AT1R–β-arrestin complex. Experimental evidence in the literature suggests that the activation of β-arrestin and blocking of G-proteins downstream of AT1R may provide additional benefits compared to Ang II blockers alone. Therefore, receptor blockers such as β-blockers, Ang II receptor blockers, and ACE inhibitors are widely used in the treatment of HF [17][2]. AT1R–β-arrestin-biased ligands, including TRV120027 and TRV120023, have demonstrated advantages over Ang II blockers in cardiac and renal function. While TRV120023 inhibits Ang II-induced cardiac hypertrophy and supports cardiomyocyte survival following ischemia injury, TRV120027 stimulates vasodilation by blocking the G-protein pathway and improves cardiac contractility [17,75,76][2][11][12]. As a result, these β-arrestin-biased ligands offer promising new HF therapies.

2. Myocardial Ischemia

Myocardial ischemia occurs after an imbalance between the oxygen supply and demand in the myocardium. This imbalance is responsible for myocardial infarction, arrhythmias, cardiac dysfunction, and sudden death. The obstruction of coronary blood flow due to thrombosis, coronary stenosis, and the hypercontraction of epicardial and coronary arteries lead to several clinical ischemic manifestations. Generally, GPCRs are essential for normal cellular function; however, sustained signaling may cause damage to the cardiac cells and functioning. The adrenergic receptor (AR) on the cardiomyocyte plays an important role in myocardial ischemia. These receptors are the principal regulators that activate adenylyl cyclase, enhancing cAMP and mediating cellular processes [77][13]. The adrenergic receptors are of two types: β1 and β2. Under normal conditions, β1AR, the most abundant in cardiomyocytes, comprises 80% of receptors, whereas β2AR comprises approximately 20%. In a diseased state, the stoichiometry changes to 60:40. The underlying mechanisms responsible for the loss of adenylyl cyclase functioning consist of reversible and irreversible phases. In the reversible phase, uncoupling of G-protein receptors and allosteric alteration of the catalytic subunit is observed. Meanwhile, in the irreversible step, free radicals cause alterations in adenylyl cyclase, which last for more than 30 min in ischemia. This functional imbalance of G-proteins is commonly observed in acute myocardial ischemia. β1 adrenergic receptor activate cardiac transduction pathways, leading to early myocyte hypertrophy, cardiac hypertrophy, and interstitial fibrosis when overexpressed, while β2AR signaling has cardioprotective effects. Therefore, beta-blocking agents are effectively used to treat myocardial ischemia [78][14].
Several modifications cause the ischemic myocardium’s loss of adenylate cyclase function. The reversible phase of this process is characterized by G-protein-receptor decoupling and potential allosteric changes in the catalytic subunit, which elevate the calcium levels in a compartment next to the enzymatic activity. Free radicals are assumed to be substantial, if not entirely, responsible for the permanent modification of adenylate cyclase function seen in ischemia lasting more than 30 min (global normothermic ischemia) [79][15]. Numerous investigations have demonstrated that rather than decreasing, the density of β adrenergic receptors increase in the plasmatic membranes of ischemic hearts. Acute myocardial ischemia causes the loss of high-energy phosphates, which stops beta-receptor coupling and signal transduction. As a result, there are more beta receptors on the cellular surface because exterior phenomena predominate over internal ones. During the early desensitization phase of the first pathophysiological stage of myocardial ischemia, the uncoupling of G-protein receptors is entirely stopped. Exogenous catecholamine administration to ischemic hearts cannot counteract this effect [80,81][16][17].
The activation of G-proteins by β adrenergic receptors increases enzymatic activity, whereas the activation of Gi proteins by M2 muscarinic receptors and A1 adenosine receptors decreases enzymatic activity. Adenylate cyclase inhibition lowers both its basal and stimulated activity. As a result, adenylate cyclase’s responsiveness to stimulating hormones is reduced by a tonic rise in Gi protein inhibitory activity. The adenylate cyclase system, on the other hand, becomes more responsive or sensitive when tonic inhibition is lost. In many acute myocardial ischemia models, G-proteins have been demonstrated to be functionally unbalanced. Gi protein levels rapidly lose functional activity following ischemic damage, but Gs protein levels are stable for a considerable time. Further research is necessary to understand the molecular mechanisms causing this functional impairment. Many experimental models of acute myocardial infarction (AMI) showed a general decrease in adenylate cyclase activity as ischemia progressed. Adenylate cyclase activity is independent of β adrenergic receptors and G-proteins, according to recent investigations on the development of acute ischemia. This activity is linked to protein kinase activation [82][18]. The succinylation, phosphorylation, SUMOylation, acetylation, and glutathionylation of G-proteins are all involved in the formation and progression of I/R injury and the regulation of cardiac repair [73][9].

3. Hypertension

High blood pressure, sometimes known as hypertension, is a complicated multifactorial condition. The force exerted by blood causes pathological changes in the arteries and arterioles, resulting in severe conditions such as target organ damage, atherosclerosis, and kidney diseases [83][19]. Hypertension is also considered a silent killer [84][20]. A delicate balance between vasoconstrictors and vasodilators is essential for maintaining blood pressure [85][21]. GPCRs function in vasodilation and vasoconstriction. Beta-adrenergic impairment, with alterations in receptor–G-protein interaction, is primarily responsible for the development of hypertension [86][22]. Mechanistically, GPCR ligands such as angiotensin II, endothelin 1, and vasopressin, via Gαq, stimulate the activity of phospholipase C-β to form inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). The pathogenesis of hypertension is also influenced by the acetylation, phosphorylation, O-GlcNAcylation, SUMOylation, and S-glutathionylation of G-proteins [73][9].
The binding of IP3 to its respective receptor leads to calcium efflux, while DAG promotes calcium influx by activating PKC [87][23]. These calcium levels increase myosin light chain kinase (MLCK) activity. MLCK activity is counter-balanced by phosphorylated MLC, thus acting in constriction. In addition, the activation of Rho kinase pathways also regulates blood pressure [88][24]. Conversely, adrenaline acts as a vasodilator that binds to its corresponding receptor to stimulate adenylyl cyclase via Gαs. The resulting cAMP formation activates PKC. This crosstalk between calcium efflux and influx leads to myosin–actin filament interactions for vascular smooth muscle cell contraction and relaxation. The alteration in ligand–GPCR exchange impairs the vascular smooth muscle cell contraction and relaxation processes, and altered adenylyl cyclase activity is responsible for high blood pressure [89][25].
G-proteins regulate signal transduction systems such as adenylyl cyclase/cAMP and phospholipase C (PLC)/phosphatidyl inositol turnover (PI), cardiovascular performance, and functions, such as arterial tone and responsiveness. Reports in the literature have shown that inhibitory G-proteins regulate the expression of G-proteins, stating Gi proteins as an essential contributing factor to hypertension. It has been demonstrated that elevated amounts of vasoactive peptides, such as angiotensin II (AngII), contribute to increased Gi protein expression, adenylyl cyclase signaling, and elevated blood pressure. Furthermore, increased oxidative stress in hypertension caused by Ang II may be responsible for the increased expression of Gi proteins observed in hypertension [90][26].
Alpha-adrenergic receptors are crucial for controlling blood pressure. The α-adrenergic receptor (αAR) family is composed of the α1AR (α1A, α1B, α1D) and α2AR (α2-adrenergic receptor; α2A, α2B, α2C) subfamilies [91][27]. Catecholamines bind to and activate αARs, similar to βARs. In subfamilies, α1ARs, expressed in the heart and cardiomyocyte, couple to Gαq to activate PLC to generate second messengers to increase intracellular Ca2+ levels [92][28]. The α1ARs also perform cardioprotective functions, such as hypertrophy, increased contractility, and decreased apoptosis [93][29]. Thus, it is recommended to exercise caution when using α1AR antagonists as drugs for the treatment of hypertension, as doxazosin and prazosin drugs have been associated with an increased incidence of heart failure [94][30].

4. Atherosclerosis

Atherosclerosis is a progressive disease involving the hardening and thickening of the mid- and large-sized arteries due to the accumulation of modified lipids in the arterial vessel wall and the formation of atheromatous plaques [95][31]. The atheromatous plaque consists of modified lipoproteins, foam cells, leukocytes, migrated vascular smooth muscle cells (VSMCs), necrotic cores, and calcified regions [96][32]. In the disease condition, endothelial dysfunction is the primary step, leading to endothelium impairment. An impairment in endothelium-dependent vasoconstrictors such as endothelin (ET) and thromboxane (Tx) and vasodilators can lead to abrogative coronary vascular tone [97][33]. ET binds to either of the receptors, ETA or ETB. Among them, ETA receptors have significance in the cardiovascular system. ETA receptors activate Gαq, resulting in the formation of IP3 and activation of MAPK signaling.
Moreover, these ETA receptors may inhibit adenylyl cyclase via Gi coupling. Based on this mechanism, ET receptor antagonists such as bosentan, sitaxentan, macitentan, or ambrisentan have shown a cardioprotective role. Further, G-protein-coupled receptor 124 (GPR124), an orphan receptor, plays a significant role in the development and progression of atherosclerosis by activating nitrosative stress and NLR family pyrin domain containing 3 (NLRP3) inflammasome signaling. In a study, Gong et al. (2018) suggested that GPR124 manipulation in the endothelium might lead to the delayed progression of atherosclerosis in an animal model [98][34]. This receptor can be used as a potential therapeutic target for atherosclerotic pathologies. In a recent review, Zhou et al. (2019) discussed the role of lysophosphatidic acid (LPA) and its receptors in the pathophysiology of atherosclerosis [99][35]. LPA is generated during the metabolism of lipids and accelerated by activated platelets, an essential step in atherosclerotic initiation and development, respectively. The extended role of GPCR transactivation of tyrosine and serine/threonine kinase growth factor receptors have been recognized. For instance, LPA-enhanced monocyte chemotactic protein-1 expression is mediated via a Gαi-RhoA-ROCK-NF-κB-dependent signaling pathway [100][36]. Consequently, the LPA receptor might be a beneficial therapeutic agent to halt the progression of atherosclerosis. GPCR agonists and antagonists are used to treat various cardiovascular conditions, and the currently available drugs used for hypertension, heart failure, and atherosclerosis are listed in Table 21.
Table 21.
GPCR-targeted drugs used for cardiovascular diseases.
Drug(s) Condition Target Reference
Irbesartan (Avapro) Hypertension Angiotensin II [101][37]
Losartan Hypertension Angiotensin II [102][38]
Vasomera (PB1046), vasoactive intestinal peptide Hypertension VIP and PACAP receptor family: VIPR1, VIPR2 [103][39]
Serelaxin Heart failure Relaxin receptor:

RXFP1, RXFP2		 [103][39]
TRV120027 Heart failure Angiotensin II [104][40]
Plozalizumab Atherosclerosis CCR2 [105][41]
Alfuzosin,

Terazosin		 Hypertension Adrenoreceptor:

Alpha-1		 [106][42]
Clonidine, Bisoprolol, Betaxolol Hypertension Adrenoreceptor:

Alpha-2		 [106][42]
Metoprolol, Atenolol Hypertension Adrenoreceptor:

Beta-1		 [106][42]
Atropine, Isoproterenol

Forskolin

Acetylcholine		 Heart rate reduction Muscarinic receptors:

Gαq (M1, M3, M5), Gαi (M2, M4)		 [17,[2107]][43]
Gs and Gi protein changes are linked to coronary artery disease. However, the relationship between Gs and Gi proteins needs to be clarified. Several studies have found that patients with coronary artery disease have either decreased Gs proteins and normal Gi proteins or increased Gi proteins and normal Gs proteins. It is critical to note that higher Gi protein levels are associated with more severe coronary artery deterioration than lower Gs protein levels [108][44]. Members of the Ras protein superfamily, such as Rho proteins, play a role in the pathophysiology of atherosclerosis. The interaction of cytokines, chemokines, and immune cells such as monocytes, macrophages, lipid droplets, and foam cells causes atherosclerosis. The Rho GTPase regulates and acts as a molecular switch for ROCK interaction and GTP-bound conformation in these atherosclerosis-related cells. On the other hand, GTPase-activating proteins and guanine nucleotide dissociation inhibitors inactivate Rho GTPase [109][45]. The acetylation, phosphorylation, nitrosylation, SUMOylation, and S- glutathionylation of G-proteins contribute to atherosclerosis [73][9].

5. Stroke

Stroke, or cerebral ischemia, is a leading cause of global mortality. It occurs due to ischemic insults and the blockage of a major cerebral artery due to the formation of a thrombus or an embolism. Loss of blood flow and tissue death occurs due to oxygen and glucose deprivation [110,111][46][47]. Evidence in the literature suggests a substantial role of GPCRs in the pathophysiology of stroke. More than 90% of GPCRs are expressed in the brain, and their roles have been identified in several processes, including immune regulation, cognition, synaptic transmission, and pain. GPCR ligands, such as oxytocin, serotonin, muscarinic acetylcholine, and cholinergic, play a vital role in activating intracellular signaling pathways [112,113][48][49]. For instance, serotonin is a neurotransmitter with both a protective and detrimental role in ischemic brain injury. All the serotonin receptors are coupled to Gαi/o, Gαs, and Gαq/11 proteins [114][50]. Activated serotonin receptors stimulate Gi/Go proteins, which leads to the inhibition of adenylyl cyclase, thereby reducing cAMP formation. This process reduces the phosphorylation of ion channels and neuronal excitation [115][51]. Studies have shown the neuroprotective benefits of serotonin agonists such as piclozotan and repinotan against ischemic brain injury [116][52].
Another example is dopamine, a neurotransmitter in the brain that controls locomotor activity, learning, and memory processes, along with positive reinforcement [117][53]. Dopaminergic receptors are of five types: D1–D5. D1 and D5 are coupled to Gs proteins, which further activate adenylyl cyclase and PKA, while other receptors are coupled to Gi/o proteins and inhibit adenylyl cyclase and PKA [118,119][54][55]. Thus, some GPCR agonists and antagonists have neuroprotective benefits, and their receptors are considered drug targets [120][56].

6. Peripheral Artery Disease

Peripheral artery disease (PAD) is the narrowing or blockage of vessels due to fatty plaque build-up, i.e., an atherosclerotic disease that affects blood vessels in the arms and legs and excludes coronary circulation [121][57]. The role of GPCRs in atherosclerosis is similar to that of GPCRs in PAD. GPCRs, such as adenosine receptors, are expressed in human organs. There are four significant subtypes of adenosine receptors: A1R, A2aR, A2bR, and A3R [122][58]. A1R and A3R function through Gi, whereas A2R couples to Gs. Stimulation of adenosine receptors releases Gβγ subunits, which play an essential role in cell growth and vascular remodeling. A1R interacts with PLC, influencing IP3 and calcium release. Thus, it is directly or indirectly involved in modulating calcium potassium channels [17,123][2][59]. Therefore, adenosine agonists and antagonists may have a cardioprotective role in therapeutics [124][60].

7. Restenosis

Restenosis is the re-narrowing of the arterial lumen following a vascular intervention intended to treat lesions, such as direct repair (patch angioplasty, endarterectomy) and intraluminal repair (balloon angioplasty, atherectomy, stent angioplasty). Restenosis also results from thrombosis, elastic recoil, remodeling, and intimal hyperplasia [125,126][61][62]. In restenosis, G-protein signaling is transient and followed by desensitization and receptor internalization. Beta-arrestin (βarr) is abundantly expressed in cardiac muscles in two isoforms: βarr1 and βarr2 (arrestin-2 and -3, respectively) [127][63]. β-arr binds to the receptor’s phosphorylated residues and at the intracellular core of the heterotrimeric G-protein binding site. This results in the steric blocking of G-protein binding to the receptor. Thus, β-arr recruitment leads to the uncoupling of G-proteins and signaling desensitization. In addition, β-arr recruits clathrin-coated pit (CCP) proteins such as clathrin heavy chain and the clathrin adapter protein-2 (AP2), which is followed by desensitization and receptor internalization [128,129][64][65]. Besides this, GPCR agonists such as angiotensin II and alpha-thrombin have also been implicated in restenosis [130][66]. In restenosis, heterotrimeric G-proteins such as Gβγ are involved in the activation of mitogen-activated protein (MAP) kinases and proliferation of vascular smooth muscle (VSM) cells. In addition, βarrestin (βarr)-1 and -2 (βarrs) are universal GPCRs expressed abundantly in the myocardium and act as molecular switches for G-protein-dependent to G-protein-independent signaling processes. βARs and AT1R have cardioprotective benefits as these molecules attenuate apoptosis [131][67].

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