Calcium, calpains, and cardiac hypertrophy: a new link.

Letters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment.ernier et al assessed the effects of calpain inhibition on angio-tensin (Ang) II–induced cardiovascular remodeling. 1 These authors used transgenic mice expressing high levels of calpastatin to inhibit Ang II– dependent calpain activation. They show that prevention of Ang II–induced calpain activation is associated with impaired nuclear factor (NF)-␬B activation in heart tissue, which eventually leads to decreased Ang II–induced cardiac hypertrophy. This finding adds substantial novel information to our understanding of how calpains might be involved in the complex regulation of cardiac hypertrophy. However, compelling evidence as to how calpains are activated by Ang II in the myocardium and how the calpain/calpastatin system is linked to NF-␬B activation is not provided. In the May 23, 2008 issue of Circulation Research, we show that Ang II induces calcium release via the inositol 1,4,5-trisphosphate receptor (InsP 3 R) pathway in cardiomyocytes and that impaired InsP 3 R-dependent calcium release after chromogranin B (CGB) knockdown attenuates NF-␬B activation and leads to decreased production of brain natriuretic peptide (BNP). 2 Here, we discuss the convergent results of these 2 studies and show that calpain/calpastatin and CGB may be important for developing new strategies in the prevention and treatment of cardiovascular disease. The calpain/calpastatin system in the heart, and particularly its potential role in the complex regulation of cardiac hypertrophy, is only poorly understood. Calpains are calcium-activated cys-teine proteases present in the cytosol as inactive proenzymes. Two isoforms (␮-and m-calpain) are ubiquitously expressed, whereas the other isoforms are tissue-specific. Calpain activity is tightly controlled by its endogenous inhibitor calpastatin. 3 Although these common principles in calpain regulation are well described, activation and downstream signaling of calpain in the myocardium are not fully understood. In the heart, 2 transcription factors play central roles in the regulation of cardiac hypertrophy, nuclear factor of activated T-cells (NFAT) and NF-␬B. 4 It is generally accepted that calpain-dependent activation of the serine/threonine protein phosphatase calcineurin controls NFAT activity in cardiomyocytes 5 ; however, the role of calpain-dependent NF-␬B activation in the heart is not established. Recent in vitro studies suggest calpain mediates degradation of the cytosolic NF-␬B inhibitor I␬B␣, a step that is a prerequisite in the activation of NF-␬B. 6 We show that impaired InsP 3 R-dependent calcium release …