Chromogranins and Inositol 1,4,5-Trisphosphate-Dependent Ca2+-Signaling in Cardiomyopathy and Heart Failure

Cardiomyocytes contain secretory granules in which chromogranins and several types of natriuretic peptides and growth factors are stored in addition to high Ca2+ concentrations. Yet the expression and serum levels of chromogranins and natriuretic peptides have been closely correlated with pathological cardiac hypertrophy and heart failure. Moreover, in distinction from the physiological cardiac hypertrophy that appears not to involve inositol 1,4,5-trisphosphate (IP3) production as the primary signaling step, accumulating evidence underscores the central role of IP3-induced intracellular Ca2+ releases in cardiomyocytes in the development of pathological cardiac hypertrophy. Consistent with this observation, chronic treatment of cardiomyocytes with G-protein coupled receptor agonists endothelin-1, angiotensin II, or phenylephrine, agents that are known to produce intracellular IP3, leads to cardiomyopathy and heart failure. In particular, the IP3-induced Ca2+ release inside the nucleus has been suggested to initiate a series of nuclear activities, including 1) Ca2+-calmodulin (CaM) mediated protein kinase II (CaMKII) activation, 2) activation of transcription factors such as myocyte enhancer factor-2 (MEF-2) and nuclear factor kappa B (NF-kappa B), and 3) increased production of chromogranins, natriuretic peptides, and growth factors, which eventually lead to pathological hypertrophy. Although secretory granules function as the major IP3-sensitive intracellular Ca2+ store and the IP3-mediated Ca2+ release from secretory granules in cardiomyocytes contributes to secretion of chromogranins and natriuretic peptides, the direct cause of pathological hypertrophy appears to be due to the IP3-induced Ca2+ release from the small nucleoplasmic IP3-sensitive Ca2+ store vesicles, thereby initiating the Ca2+-activated nuclear activities that lead to formation of more secretory granules, pathologic enlargement of cardiomyocytes, and heart failure.