Catestatin Gly364Ser Variant Alters Systemic Blood Pressure and the Risk for Hypertension in Human Populations via Endothelial Nitric Oxide Pathway

Kiranmayi, M and Chirasani, V R and Allu, P K R and Subramanian, L and Martelli, E E and Sahu, B S and Vishnuprabu, D and Kumaragurubaran, R and Sharma, S K and Bodhini, D and Dixit, M and Munirajan, A K and Khullar, M and Radha, V and Mohan, V and Mullasari, A S and Naga Prasad, S V and Senapati, S and Mahapatra, N R (2016) Catestatin Gly364Ser Variant Alters Systemic Blood Pressure and the Risk for Hypertension in Human Populations via Endothelial Nitric Oxide Pathway. Hypertension, 68 (2). p. 334. ISSN 0194-911X



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 (ageadjusted 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.

Item Type:Article
Official URL/DOI:
Uncontrolled Keywords:chromogranin A; genetic association study; genetic variation; hypertension; nitric oxide
Subjects:Genetics and Diabetes
Divisions:Department of Epidemiology
Department of Advanced Research Biochemistry
ID Code:1003
Deposited By:surendar radha
Deposited On:08 Aug 2016 11:46
Last Modified:08 Aug 2016 11:46

Repository Staff Only: item control page