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Pancreastatin (PST), a chromogranin A-derived potent physiological dysglycemic peptide, regulates glucose/insulin homeostasis. We have identified a nonsynonymous functional PST variant (p.Gly297Ser; rs9658664) that occurs in a large section of human populations. Association analysis of this single nucleotide polymorphism with cardiovascular/metabolic disease states in Indian populations (n = 4,300 subjects) displays elevated plasma glucose, glycosylated hemoglobin, diastolic blood pressure, and catecholamines in Gly/Ser subjects as compared with wild-type individuals (Gly/Gly). Consistently, the 297Ser allele confers an increased risk (∼1.3-1.6-fold) for type 2 diabetes/hypertension/coronary artery disease/metabolic syndrome. In corroboration, the variant peptide (PST-297S) displays gain-of-potency in several cellular events relevant for cardiometabolic disorders (e.g., increased expression of gluconeogenic genes, increased catecholamine secretion, and greater inhibition of insulin-stimulated glucose uptake) than the wild-type peptide. Computational docking analysis and molecular dynamics simulations show higher affinity binding of PST-297S peptide with glucose-regulated protein 78 (GRP78) and insulin receptor than the wild-type peptide, providing a mechanistic basis for the enhanced activity of the variant peptide. In vitro binding assays validate these in silico predictions of PST peptides binding to GRP78 and insulin receptor. In conclusion, the PST 297Ser allele influences cardiovascular/metabolic phenotypes and emerges as a novel risk factor for type 2 diabetes/hypertension/coronary artery disease in human populations. [ABSTRACT FROM AUTHOR]

Catestatin (CST), a 21-amino acids physiological peptide, has emerged as a key modulator of cardiovascular functions due to its anti-hypertensive and cardioprotective properties. However, the ramifications of the most common human variant of CST (viz., Gly364Ser) on cardiovascular pathophysiology remain partially understood. In this study, hypertension was induced in uninephrectomized rats by treatment with deoxycorticosterone-acetate and sodium chloride (DOCA-salt). The DOCA-salt-induced hypertensive (DSHR) animals were then intraperitoneally administered with either CST wild-type (CST-WT) or 364Ser variant (CST-Ser) peptide. CST-Ser was profoundly less effective than CST-WT in rescuing the elevated systolic blood pressure [from ∼211 mmHg to ∼176 mmHg, p < 0.0001 (CST-Ser) versus ∼116 mmHg, p < 0.0001 (CST-WT)] and heart rate [from ∼356 bpm to ∼314 bpm, p = 0.66 (CST-Ser) versus ∼276 bpm, p = 0.02 (CST-WT)]. CST-Ser also showed diminished effects in lowering diastolic blood pressure and mean arterial pressure in the DSHR animals. Furthermore, CST-Ser was inefficient/markedly less potent in rescuing the impaired contractile and diastolic function in DSHR animals [improvements in the contractility index by ∼22 s-1 (CST-Ser), p = 0.15 versus by ∼84 s-1 (CST-WT), p < 0.0001 and decrease in end-diastolic pressure by ∼4 mmHg (CST-Ser), p = 0.015 versus by ∼14 mmHg (CST-WT), p < 0.0001]. Moreover, CST-Ser exerted less potent anti-inflammatory effects on the DSHR hearts than CST-WT. These findings are in concordance with the elevated systolic/diastolic blood pressure observed in Ser variant carriers from various human populations. This study provides compelling evidence for the diminished anti-hypertensive and cardioprotective effects of the CST-Gly364Ser variant., (© 2024 The Author(s).)