Chromogranin B regulates calcium signaling, nuclear factor kappaB activity, and brain natriuretic peptide production in cardiomyocytes

Circ Res. 2008 May 23;102(10):1230-8. doi: 10.1161/CIRCRESAHA.107.166033. Epub 2008 Apr 17.

Abstract

Altered regulation of signaling pathways can lead to pathologies including cardiac hypertrophy and heart failure. We report that neonatal and adult cardiomyocytes express chromogranin B (CGB), a Ca(2+) binding protein that modulates Ca(2+) release by the inositol 1,4,5-trisphosphate receptor (InsP(3)R). Using fluorescent Ca(2+) indicator dyes, we found that CGB regulates InsP(3)-dependent Ca(2+) release in response to angiotensin II, an octapeptide hormone that promotes cardiac hypertrophy. ELISA experiments and luciferase reporter assays identified angiotensin II as a potent inducer of brain natriuretic peptide (BNP), a hormone that recently emerged as an important biomarker in cardiovascular disease. CGB was found to regulate angiotensin II-stimulated and basal secretion, expression and promoter activity of BNP that depend on the InsP(3)R. Moreover, we provide evidence that CGB acts via the transcription activity of nuclear factor kappaB in an InsP(3)/Ca(2+)-dependent manner but independent of nuclear factor of activated T cells. In vivo experiments further showed that cardiac hypertrophy induced by angiotensin II, a condition characterized by increased ventricular BNP production, is associated with upregulation of ventricular CGB expression. Overexpression of CGB in cardiomyocytes, in turn, induced the BNP promoter. The evidence presented in this study identifies CGB as a novel regulator of cardiomyocyte InsP(3)/Ca(2+)-dependent signaling, nuclear factor kappaB activity, and BNP production.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Angiotensin II / metabolism
  • Angiotensin II / pharmacology
  • Animals
  • Calcium / metabolism
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology*
  • Cardiomegaly / metabolism*
  • Cardiomegaly / pathology
  • Cells, Cultured
  • Chromogranin B / metabolism*
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • NF-kappa B / metabolism*
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism
  • Natriuretic Peptide, Brain / genetics
  • Natriuretic Peptide, Brain / metabolism*
  • Promoter Regions, Genetic / physiology
  • Rats
  • Transcription, Genetic / physiology
  • Vasoconstrictor Agents / metabolism
  • Vasoconstrictor Agents / pharmacology

Substances

  • Chromogranin B
  • Inositol 1,4,5-Trisphosphate Receptors
  • NF-kappa B
  • NFATC Transcription Factors
  • Vasoconstrictor Agents
  • chromogranin B, rat
  • natriuretic peptide precursor type B, rat
  • Angiotensin II
  • Natriuretic Peptide, Brain
  • Calcium