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, Lakshmi Subramanian, Elizabeth E. Martelli, Bhavani S. Sahu, Durairajpandian Vishnuprabu, Rathnakumar Kumaragurubaran, Saurabh Sharma, Dhanasekaran Bodhini, Madhulika Dixit, Arasambattu K. Munirajan, Madhu Khullar, Venkatesan Radha, Viswanathan Mohan, Ajit S. Mullasari, Sathyamangla V.Naga Prasad, Sanjib Senapati, Nitish R. Mahapatra

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)334-347
Number of pages14
JournalHypertension
Volume68
Issue number2
DOIs
StatePublished - Aug 1 2016

Bibliographical note

Funding Information:
This work was supported by grants BT/PR9546/MED/12/349/2007 and BT/PR12820/BRB/10/726/2009 from the Department of Biotechnology (DBT), Government of India. This work was also supported in part by grants SR/SO/HS-084/2013A from the Science and Engineering Research Board, BT/PR4820/MED/12/622/2013 from DBT, Government of India, and NIH RO1 HL HL089473.

Publisher Copyright:
© 2016 American Heart Association, Inc.

Keywords

  • chromogranin A
  • genetic association study
  • genetic variation
  • hypertension
  • nitric oxide

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