These multitude of effects establish CST as a master regulator of cardiovascular functions.
Catestatin (CST), an endogenous anti-hypertensive/anti-adrenergic peptide, is a novel regulator of cardiovascular physiology. Here, we report case-control studies in two geographically/ethnically-distinct Indian populations (n≈4000) that showed association of the naturally-occurring human CST-Gly364Ser variant with increased risk for hypertension (age-adjusted odds ratios: 1.483, p=0.009 and 2.951, p=0.005). Consistently, 364Ser allele carriers displayed elevated systolic (up to ~8 mmHg, p=0.004) and diastolic (up to ~6 mmHg, p=0.001) blood pressure. The variant allele was also found to be in linkage disequilibrium with other functional SNPs in the CHGA promoter and nearby coding region. Functional characterization of the Gly364Ser variant was carried out using cellular/molecular biological experiments (viz. peptide-receptor binding assays, nitric oxide [NO], phospho extracellular regulated kinase [ERK] and phospho endothelial nitric oxide synthase [eNOS] estimations) and computational approaches (molecular dynamics simulations for structural analysis of wild-type [CST-WT] and variant [CST-364Ser] peptides, and docking of peptide/ligand with beta-adrenergic receptors [ADRB1/2]). CST-WT and CST-364Ser peptides differed profoundly in their secondary structures and showed differential interactions with ADRB2; while CST-WT displaced the ligand bound to ADRB2, CST-364Ser failed to do the same. Furthermore, CST-WT significantly inhibited ADRB2-stimulated ERK activation suggesting an antagonistic role on ADRB2 unlike CST-364Ser. Consequently, CST-WT was more potent in NO production in human-umbilical-vein-endothelial-cells as compared to CST-364Ser. This NO producing ability of CST-WT was abrogated by ADRB2 antagonist ICI 118551. In conclusion, CST-364Ser allele enhanced the risk for hypertension in human populations, possibly via diminished endothelial NO production due to altered interactions of CST-364Ser peptide with ADRB2 as compared to CST-WT.
The acidic glycoprotein chromogranin A (CHGA) is co-stored/co-secreted with catecholamines and crucial for secretory vesicle biogenesis in neuronal/neuroendocrine cells. CHGA is dysregulated in several cardiovascular diseases, but the underlying mechanisms are not well established. Here, we sought to identify common polymorphisms in the promoter and to explore the mechanistic basis of their plausible contribution to regulating CHGA protein levels in circulation. Resequencing of the promoter in an Indian population ( = 769) yielded nine single-nucleotide polymorphisms (SNPs): G-1106A, A-1018T, T-1014C, T-988G, G-513A, G-462A, T-415C, C-89A, and C-57T. Linkage disequilibrium (LD) analysis indicated strong LD among SNPs at the -1014, -988, -462, and -89 bp positions and between the -1018 and -57 bp positions. Haplotype analysis predicted five major promoter haplotypes that displayed differential promoter activities in neuronal cells; specifically, haplotype 2 (containing variant T alleles at -1018 and -57 bp) exhibited the highest promoter activity. Systematic computational and experimental analyses revealed that transcription factor c-Rel has a role in activating the promoter haplotype 2 under basal and pathophysiological conditions ( inflammation and hypoxia). Consistent with the higher promoter activity of haplotype 2, individuals carrying this haplotype had higher plasma CHGA levels, plasma glucose levels, diastolic blood pressure, and body mass index. In conclusion, these results suggest a functional role of the promoter haplotype 2 (occurring in a large proportion of the world population) in enhancing CHGA expression in haplotype 2 carriers who may be at higher risk for cardiovascular/metabolic disorders.
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