Disruption of calpain reduces lipotoxicity-induced cardiac injury by preventing endoplasmic reticulum stress

Abstract

Diabetes and obesity are prevalent in westernized countries. In both conditions, excessive fatty acid uptake by cardiomyocytes induces cardiac lipotoxicity, an important mechanism contributing to diabetic cardiomyopathy. This study investigated the effect of calpain disruption on cardiac lipotoxicity. Cardiac-specific capns1 knockout mice and their wild-type littermates (male, age of 4 weeks) were fed a high fat diet (HFD) or normal diet for 20 weeks. HFD increased body weight, altered blood lipid profiles and impaired glucose tolerance comparably in both capns1 knockout mice and their wild-type littermates. Calpain activity, cardiomyocyte cross-sectional areas, collagen deposition and triglyceride were significantly increased in HFD-fed mouse hearts, and these were accompanied by myocardial dysfunction and up-regulation of hypertrophic and fibrotic collagen genes as well as pro-inflammatory cytokines. These effects of HFD were attenuated by disruption of calpain in capns1 knockout mice. Mechanistically, deletion of capns1 in HFD-fed mouse hearts and disruption of calpain with calpain inhibitor-III, silencing of capn1, or deletion of capns1 in palmitate-stimulated cardiomyocytes prevented endoplasmic reticulum stress, apoptosis, cleavage of caspase-12 and junctophilin-2, and pro-inflammatory cytokine expression. Pharmacological inhibition of endoplasmic reticulum stress diminished palmitate-induced apoptosis and pro-inflammatory cytokine expression in cardiomyocytes. In summary, disruption of calpain prevents lipotoxicity-induced apoptosis in cardiomyocytes and cardiac injury in mice fed a HFD. The role of calpain is mediated, at least partially, through endoplasmic reticulum stress. Thus, calpain/endoplasmic reticulum stress may represent a new mechanism and potential therapeutic targets for cardiac lipotoxicity.

Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy

“…Although skeletal muscle atrophy probably not regulated by a single mechanism, but a complex one, the calcium-dependent cysteine proteases, calpain also considered as one of the main culprit of protein degradation [ 36 ]. A growing evidence depicted that both calpain and the ubiquitin-proteasome system act synergistically and in a coordinated manner during sepsis induced muscle proteolysis [ 37 ]. The present study findings also described a significant increase in calpain activity on 14d CHH exposure, which was accompanied by an increase in intracellular [Ca 2+ ] (~3 fold), which is rate limiting co-factor of calpain.…”

Over-expression of calpastatin attenuates myocardial injury following myocardial infarction by inhibiting endoplasmic reticulum stress

“…During heart failure, ER stress in cardiomyocytes causes specific morphological changes, suggesting its involvement in cardiac pathophysiologic processes (4)(5)(6). These changes in ER morphology were concomitant with modifications of molecules, such as tumor necrosis factor-α (TNF-α), caspase 3, p53 upregulated modulator of apoptosis (PUMA), and glucose regulated protein 94 (GRP 94), that regulate ER stress-related pathological processes including hypoxia, production of reactive oxygen species (ROS), enhanced protein synthesis, and induction of lipotoxicity (6,7). ER stress has also been detected in both hypertrophic and failure phases induced by transverse aortic constriction in an animal model (5), and is potentially associated with the pathogenesis of human heart failure, as evidenced by the increased expression of binding immunoglobulin protein (BIP, also referred to as GRP78), an ER chaperone and signaling regulator (8), in failing human hearts (4,5).…”

Targeting Calpain for Heart Failure Therapy

“…For example, transgenic overexpression of the endogenous calpain inhibitor, calpastatin, protects against myocardial dysfunction in models such as myocardial infarction (26) and endotoxemia (27) . The Peng group has also used genetic deletion of calpain-4, a regulatory subunit for both calpain-1 and calpain-2, to demonstrate the protective effect of inhibiting calpain activity on cardiac function, deleterious reactive oxygen species production, endoplasmic reticulum stress, and mitochondrial metabolic function in multiple different experimental models, including diabetes, ischemia (8) , high-fat diet (28) , and endotoxemia (29) . Studies have also explored the use of MDL-28170 in the acute heart failure model of cardiac ischemia/reperfusion injury and found that administration of the calpain inhibition at the time of injury limits ischemia/reperfusion-induced infarction (30) .…”