Calpain Protects the Heart from Hemodynamic Stress

Abstract

Calpains make up a family of Ca 2؉ -dependent intracellular cysteine proteases that include ubiquitously expressed -and m-calpains. Both are heterodimers consisting of a distinct large catalytic subunit (calpain 1 for -calpain and calpain 2 for m-calpain) and a common regulatory subunit (calpain 4). The physiological roles of calpain remain unclear in the organs, including the heart, but it has been suggested that calpain is activated by Ca 2؉ overload in diseased hearts, resulting in cardiac dysfunction. In this study, cardiac-specific calpain 4-deficient mice were generated to elucidate the role of calpain in the heart in response to hemodynamic stress. Cardiac-specific deletion of calpain 4 resulted in decreased protein levels of calpains 1 and 2 and showed no cardiac phenotypes under base-line conditions but caused left ventricle dilatation, contractile dysfunction, and heart failure with interstitial fibrosis 1 week after pressure overload. Pressure-overloaded calpain 4-deficient hearts took up a membrane-impermeant dye, Evans blue, indicating plasma membrane disruption. Membrane repair assays using a two-photon laser-scanning microscope revealed that calpain 4-deficient cardiomyocytes failed to reseal a plasma membrane that had been disrupted by laser irradiation. Thus, the data indicate that calpain protects the heart from hemodynamic stresses, such as pressure overload.

Calpain-dependent Cleavage of N-cadherin Is Involved in the Progression of Post-myocardial Infarction Remodeling

“…However, cardiac-specific Capns1 knock-out mice were susceptible for hemodynamic stress-induced myocardial injury because of defective membrane repair, indicating that calpains play a beneficial role as well (43). Because calpain activity in sham-operated hearts was indistinguishable between Cast Ϫ/Ϫ and Cast ϩ/ϩ hearts (Fig.…”

Resuscitation of a dead cardiomyocyte

“…Pressure overload via trans-aortic constriction (TAC) caused ventricular dilation, interstitial fibrosis, heart failure and contractile dysfunction. Calpain 4-deficient cardiomyocytes also failed to reseal a break in the plasma membrane, showing plasma membrane dysfunction [21]. We speculate that intermolecular signaling may occur between regional calpain isoforms, naturally causing a decrease in calpain 1 and 2.…”

Sterile Inflammation and Degradation Systems in Heart Failure

“…32 In contrast, we reported that calpains protected the heart from hemodynamic stress induced by TAC and were required for plasma membrane maintenance using our cardiac-specific calpain 4/Capns1-deficient mice. 33 Caspases consist of a cysteine protease cascade that is well defined as an essential proteolytic pathway to induce apoptosis. 34 In addition to apoptosis, caspases are involved in tissue differentiation, regeneration, neural development, genome stability maintenance, autophagy, and inflammation.…”