Catestatin Gly364Ser Variant Alters Systemic Blood Pressure and the Risk for Hypertension in Human Populations via Endothelial Nitric Oxide Pathway
Malapaka Kiranmayi,Venkat R. Chirasani,Prasanna K.R. Allu,Prasanna K.R. Allu,Lakshmi Subramanian,Elizabeth E Martelli,Bhavani S. Sahu,Bhavani S. Sahu,Durairajpandian Vishnuprabu,Rathnakumar Kumaragurubaran,Saurabh Sharma,Dhanasekaran Bodhini,Madhulika Dixit,Arasambattu Kannan Munirajan,Madhu Khullar,Venkatesan Radha,Viswanathan Mohan,Ajit S. Mullasari,Sathyamangla V. Naga Prasad,Sanjib Senapati,Nitish R. Mahapatra +20 more
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TLDR
CST-364Ser allele enhanced the risk for hypertension in human populations, possibly via diminished endothelial NO production because of altered interactions of CST-364 Ser peptide with ADRB2 as compared with CST-WT.Abstract:
Catestatin (CST), an endogenous antihypertensive/antiadrenergic peptide, is a novel regulator of cardiovascular physiology. Here, we report case–control studies in 2 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 mm Hg; P =0.004) and diastolic (up to ≈6 mm Hg; P =0.001) blood pressure. The variant allele was also found to be in linkage disequilibrium with other functional single-nucleotide polymorphisms in the CHGA promoter and nearby coding region. Functional characterization of the Gly364Ser variant was performed using cellular/molecular biological experiments (viz peptide–receptor binding assays, nitric oxide [NO], phosphorylated extracellular regulated kinase, and phosphorylated endothelial NO synthase 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 β-adrenergic receptors [ADRB1/2]). CST-WT and CST-364Ser peptides differed profoundly in their secondary structures and showed differential interactions with ADRB2; although CST-WT displaced the ligand bound to ADRB2, CST-364Ser failed to do the same. Furthermore, CST-WT significantly inhibited ADRB2-stimulated extracellular regulated kinase activation, suggesting an antagonistic role towards ADRB2 unlike CST-364Ser. Consequently, CST-WT was more potent in NO production in human umbilical vein endothelial cells as compared with 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 because of altered interactions of CST-364Ser peptide with ADRB2 as compared with CST-WT.read more
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