Role of Catestatin in the Cardiovascular System and Metabolic Disorders

Abstract

Catestatin is a multifunctional peptide that is involved in the regulation of the cardiovascular and immune systems as well as metabolic homeostatis. It mitigates detrimental, excessive activity of the sympathetic nervous system by inhibiting catecholamine secretion. Based on in vitro and in vivo studies, catestatin was shown to reduce adipose tissue, inhibit inflammatory response, prevent macrophage-driven atherosclerosis, and regulate cytokine production and release. Clinical studies indicate that catestatin may influence the processes leading to hypertension, affect the course of coronary artery diseases and heart failure. This review presents up-to-date research on catestatin with a particular emphasis on cardiovascular diseases based on a literature search.

Keywords: cardiovascular system; catestatin; coronary artery disease; heart failure; hypertension; immunometabolism; metabolic disorder.

Figure 1

Mechanism of action of catestatin based on in vitro and in vivo animal studies. (A) Injection of Cts into the CVLM or the central amygdala (not shown) of rats decreases sympathetic barosensitivity and attenuates peripheral chemoreflex with consequent hypotension. On the other hand, injection of Cts into the RVLM increases barosensitivity and attenuates chemosensitivity with consequent elevation of blood pressure (14). (B) Cts inhibits CA release by binding to nicotinic acetylcholine receptors that block Na⁺ uptake (15) as well as due to PACAP stimulation (13). (C) Cts inhibits the PKA/PLN signaling pathway and induces NO synthesis in myocardiocytes, and the released NO reduces cellular Ca²⁺, resulting in decreased cardiac contractility (16) and relaxation of ET-1 preconstricted coronaries (17). Cts also induces glucose uptake and Glut4 translocation (18). (D) Cts induces NO synthesis from endothelial cells, and activates ACE2, which has an anti-atherogenic effect (15, 16, 19). (E) Cts induces histamine release leading to vasodepression and transient inotropic effect in myocardiocytes (16). (F) Treatment with Cts results in polarization of macrophages toward an anti-inflammatory phenotype (20). Macrophages also produce Cts (21). (G) Cts up-regulates genes promoting fatty acid oxidation (22) and enhances insulin-induced Akt phosphorylation, which helps in overcoming ER stress and achieving insulin sensitivity (23). (H) Cts promotes lipid flux from adipose tissue toward the liver and lowers plasma leptin in Chga-KO mice leading to resensitization of leptin receptors (22). (I) PMNs are able to produce and secrete CgA-derived peptides, including Cts, which may penetrate into PMNs and activate the release of innate immune factors (24). A1-7, Angiotensin 1-7; AII, Angiotensin II; AC, Adenylyl cyclase; ACE2, activates angiotensin-converting enzyme-2; Ach, acetylcholine; Acox1, acyl-CoA oxidase 1; Akt, Protein kinase B; AMPK, AMP-activated protein kinase; ARG1, Arginase 1 gene; β1AR, β1 adrenergic receptors; β2AR, β2 adrenergic receptors; Ca²⁺, calcium ions; cAMP, adenosine monophosphate; CAs, catecholamines; CCL2, C-C Motif Chemokine Ligand 2; CD36, cluster of differentiation 36; CgA, Chromogranin A; CgB, Chromogranin B; Chga-KO, Chromogranin knockout; cGMP, cyclic guanosine monophosphate; Cpt1α, Carnitine palmitoyltransferase 1α; CREB, cAMP response element-binding protein; Cts, catestatin; CVLM, caudal ventrolateral medulla; DNL, de novo lipogenesis; eNOS, endothelial nitric oxide synthase; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinas; ET-1, endothelin 1; ETAR, Endothelin receptor type A; ETBR, Endothelin receptor type B; FAO, Fatty acid oxidation; FAU, Fatty acid uptake; Gpat4, lipogenic gene glycerol-3-phosphate acyltransferase; GTP, guanosine-5' triphosphate; H, histamine; ICAM1, Intercellular Adhesion Molecule 1; IFNG, Interferon Gamma gene; IL-4, interleukin 4; IL-6, interleukin 6; IL-10, interleukin 10; iPLA2, calcium-independent phospholipase A2; ITGAX, Integrin Subunit Alpha X; LepR, Leptin receptor; LysoPL, lysophospholipids; MMP-2 Matrix Metallopeptidase 2; MMP-9, Matrix metallopeptidase 9; MRC1, Mannose Receptor C-Type 1 gene; MRGPRX2, Mas-Related G Protein-Coupled Receptor-X2; Na+, sodium; NO, nitric oxide; NOS2, Nitric Oxide Synthase 2; nNOS, neuronal nitric oxide synthase; NTS, Nucleus tractus solitarius; P, phosphor; PACAP, Pituitary adenylate cyclase-activating polypeptide; PAC1R, Pituitary adenylate cyclase-activating polypeptide receptor; PDE2, Phosphodiesterase 2; Pi3K, Phosphoinositide 3-kinase; PKA, Protein kinase A; PKC, protein kinase C; PKG, protein kinase G; PLN, phospholamban; PMNs, Polymorphonuclear neutrophils; Pparα, Peroxisome proliferator-activated receptor-α; RVLM, rostral ventrolateral medulla; RyR, Ryanodine receptor; sGC, soluble guanylyl cyclase; SERCA, Sarcoplasmic reticulum Ca-ATPase; SOC, Store-Operated Calcium Channels; STAT3, Signal Transducer And Activator Of Transcription 3; TAG, Triacylglycerols; TNFa, TNF alpha gene; Ucp2, uncoupling protein 2; VCAM1, vascular cell adhesion molecule 1. Dashed arrow – inhibition; continuous arrow – stimulation.