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(Circulation Research. 2008;102:1230.)
© 2008 American Heart Association, Inc.

Cellular Biology

Chromogranin B Regulates Calcium Signaling, Nuclear Factor B Activity, and Brain Natriuretic Peptide Production in Cardiomyocytes

Felix M. Heidrich, Kun Zhang^*, Manuel Estrada^*, Yan Huang, Frank J. Giordano, Barbara E. Ehrlich

From the Departments of Pharmacology (F.M.H., K.Z., B.E.E.) and Medicine/Cardiology (Y.H., F.J.G.), Yale University, New Haven, Conn; Department of Pharmacology and Toxicology (F.M.H.), Dresden University of Technology, Germany; Neuroscience Research Centre (K.Z.), Charité Universitätsmedizin, Berlin, Germany; and Department of Physiology and Biophysics (M.E.), University of Chile, Santiago.

Correspondence to Barbara E. Ehrlich, Department of Pharmacology, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520-8066. E-mail barbara.ehrlich{at}yale.edu

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 (InsP₃R). Using fluorescent Ca²⁺ indicator dyes, we found that CGB regulates InsP₃-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 InsP₃R. Moreover, we provide evidence that CGB acts via the transcription activity of nuclear factor B in an InsP₃/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 InsP₃/Ca²⁺-dependent signaling, nuclear factor B activity, and BNP production.

Key Words: chromogranin B • calcium • inositol 1,4,5-trisphosphate receptor • nuclear factor NF-B • brain natriuretic peptide

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				F. M. Heidrich and B. E. Ehrlich Calcium, Calpains, and Cardiac Hypertrophy: A New Link Circ. Res., January 30, 2009; 104(2): e19 - e20. [Full Text] [PDF]