Abstract
Diabetes is a major risk factor for cardiovascular disease and the lysosomal cysteine protease cathepsin K plays a critical role in cardiac pathophysiology. To expand upon our previous findings, we tested the hypothesis that, knockout of cathepsin K protects against diabetes-associated cardiac anomalies. Wild-type and cathepsin K knockout mice were rendered diabetic by streptozotocin (STZ) injections. Body weight, organ mass, fasting blood glucose, energy expenditure, cardiac geometry and function, cardiac histomorphology, glutathione levels and protein levels of cathepsin K and those associated with Ca2+ handling, calcineurin/NFAT signaling, insulin signaling, cardiac apoptosis and fibrosis were determined. STZ-induced diabetic mice exhibited distinct cardiac dysfunction, dampened intracellular calcium handling, alterations in cardiac morphology, and elevated cardiomyocyte apoptosis, which were mitigated in the cathepsin K knockout mice. Additionally, cathepsin K knockout mice attenuated cardiac oxidative stress and calcineurin/NFAT signaling in diabetic mice. In cultured H9c2 myoblasts, pharmacological inhibition of cathepsin K, or treatment with calcineurin inhibitor rescued cells from high-glucose triggered oxidative stress and apoptosis. Therefore, cathepsin K may represent a potential target in treating diabetes-associated cardiac dysfunction.
Highlights
Diabetes mellitus is an independent risk factor for heart failure and is and is characterized by dilated ventricles, hypertrophic cardiomyocytes, pronounced interstitial fibrosis, diastolic dysfunction, and impaired/preserved systolic function, which leads to heart failure[1,2,3,4,5]
Liver and kidney mass were unchanged following STZ-treatment, when normalized to body weight, the mass of these organs were significantly increased compared to vehicle treatment, which was attenuated in cathepsin K knockout mice
Dilated cardiomyopathy is a cardiovascular complication in diabetic subjects, which eventually leads to heart failure[1, 2]
Summary
Diabetes mellitus is an independent risk factor for heart failure and is and is characterized by dilated ventricles, hypertrophic cardiomyocytes, pronounced interstitial fibrosis, diastolic dysfunction, and impaired/preserved systolic function, which leads to heart failure[1,2,3,4,5]. Increased expression and activity of cathepsin K has been reported in the hypertrophic and failing heart[8]. We have previously shown that knocking out cathepsin K in mice alleviates obesity and pressure overload–associated cardiac dysfunction in mice[9, 10]. The explicit role of cathepsin K in diabetic cardiovascular complications or the potential mechanisms remains unknown. In this study, we hypothesized that cathepsin K knockout protects agains cardiac structural and functional alterations induced by diabetes. We assessed the effect of deletion of cathepsin K on cardiomyocyte Ca2+ handling, oxidative stress, apoptosis and calcineurin/ NFATs (nuclear factor of activated T-cells) signaling
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