Chromogranin B in Calpain-Mediated Hypertrophic Signaling—The Chicken, the Egg, or Even Both…?

Abstract

It was with great interest that we read this focused review by Patterson and colleagues on the role of calpains in cardiac hypertrophy. Succinctly, the authors provide a comprehensive overview on the current body of evidence of how calpains are believed to be implicated in the regulation of the development of cardiac, specifically ventricular, hypertrophy and go further on to discuss potential therapeutic strategies. 1 In 2008, we studied the mechanism by which angiotensin II (Ang II) activates nuclear factor (NF)-B in cardiomyocytes to drive the hypertrophic signaling pathway and showed that this activation depends on calcium release by the inositol 1,4,5-trisphosphate (InsP 3 ) receptor (InsP 3 R). 2 Importantly, we identified the calcium storage protein chromogranin B (CGB) to be of crucial importance in shaping this InsP 3 -dependent release of calcium. Our in vitro results were supported by in vivo experiments that showed an impressive increase of ventricular CGB in Ang II-induced cardiac hypertrophy. While CGB is a well-known activator of the InsP 3 R, 3 its presence and function in cardiomyocytes had never been studied before. On the basis of the evidence presented, we proposed a crucial role for CGB in the pathophysiology of cardiac hypertrophy and heart failure (HF).In an independent, almost simultaneously published study, Letavernier and colleagues assessed the effect of calpain inhibition by its endogenous inhibitor, calpastatin, on Ang II-induced cardiac hypertrophy. 4 Using calpastatin transgenic mice expressing high levels of calpastatin, these authors elegantly showed that the prevention of Ang II-induced calpain activation is associated with impaired NF-B activation and decreased cardiac hypertrophy.On the basis of the intriguing parallels in the results of these 2 independent studies, we proposed that the missing link in cardiomyocyte calcium-dependent NF-B activation is the calcium-activated protease calpain. 5 In this relationship, Ang II triggers the InsP 3 -dependent calcium release that is specifically shaped by CGB via its functional interaction with the InsP 3 R. The CGB-modified calcium signal then activates calpain that eventually regulates NF-B activity to stimulate hypertrophic signaling (Supplemental Figure I, available online at http://circres.ahajournals.org). In this model, CGB "fine-tunes" the InsP 3 -dependent calcium signal in cardiomyocytes to selectively activate specific downstream agonists such as calpains in the context of Ang II-induced cardiac hypertrophy.In this current review, Patterson and colleagues, however, outline a relationship among Ang II, CGB, and calpain in NF-B activation that slightly, though crucially, differs from our proposed model. On the basis of the evidence presented above, we believe that it is not as Patterson and colleagues suggest that InsP 3 -dependent release of calcium and calpains turn on CGB. Rather, vice versa, we believe it currently is reasonable to propose a cascade in which CGB-in its function as activator of the InsP 3 R-shapes the Ang...

Spatio-temporal regulation of calpain activity after experimental myocardial infarction in vivo

“…The InsP 3 R controls the release of intracellularly stored calcium into the cytoplasm, that is crucial for the activation of several transcription factors including NF-ĸB [ 34 ]. An association of angiotensin II signaling, InsP 3 R mediated calcium mobilization, calpain activation and NF-ĸB related natriuretic peptide production in the myocardium has been assumed before [ 6 , 35 , 36 ]. Our data support the presence of this pathway in the infarcted myocardium.…”

“…Since calpains are calcium activated proteases, imbalances in calcium homeostasis, which e.g. occur during hypoxia, ischemia and post-ischemic reperfusion, can result in disturbed calpain activity in the myocardium [ [5] , [6] , [7] ].…”