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

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 Ca2+ binding protein that modulates Ca2+ release by the inositol 1,4,5-trisphosphate receptor (InsP(3)R). Using fluorescent Ca2+ indicator dyes, we found that CGB regulates InsP(3)-dependent Ca2+ 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 kappa B in an InsP(3)/Ca2+-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)/Ca2+-dependent signaling, nuclear factor kappa B activity, and BNP production.