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• W2806003462 abstract "Abstract The lysosomal cysteine protease Cathepsin K is elevated in humans and animal models of heart failure. Our recent studies show that whole-body deletion of Cathepsin K protects mice against cardiac dysfunction. Whether this is attributable to a direct effect on cardiomyocytes or is a consequence of the global metabolic alterations associated with Cathepsin K deletion is unknown. To determine the role of Cathepsin K in cardiomyocytes, we developed a cardiomyocyte-specific Cathepsin K-deficient mouse model and tested the hypothesis that ablation of Cathepsin K in cardiomyocytes would ameliorate the cardiotoxic side-effects of the anticancer drug doxorubicin. We used an α-myosin heavy chain promoter to drive expression of Cre, which resulted in over 80% reduction in protein and mRNA levels of cardiac Cathepsin K at baseline. Four-month-old control (Myh-Cre - ; Ctsk fl/fl ) and Cathepsin K knockout (Myh-Cre + ; Ctsk fl/fl ) mice received intraperitoneal injections of doxorubicin or vehicle, 1 week following which, body and tissue weight, echocardiographic properties, cardiomyocyte contractile function and Ca 2+ -handling were evaluated. Control mice treated with doxorubicin exhibited a marked increase in cardiac Cathepsin K, which was associated with an impairment in cardiac structure and function, evidenced as an increase in end-systolic and end-diastolic diameters, decreased fractional shortening and wall thickness, disruption in cardiac sarcomere and microfilaments and impaired intracellular Ca 2+ homeostasis. In contrast, the aforementioned cardiotoxic effects of doxorubicin were attenuated or reversed in mice lacking cardiac Cathepsin K. Mechanistically, Cathepsin K-deficiency reconciled the disturbance in cardiac energy homeostasis and attenuated NF-κB signaling and apoptosis to ameliorate doxorubicin-induced cardiotoxicity. Cathepsin K may represent a viable drug target to treat cardiac disease." @default.
• W2806003462 created "2018-06-13" @default.
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• W2806003462 date "2018-06-07" @default.
• W2806003462 modified "2023-10-14" @default.
• W2806003462 title "Cardiomyocyte-specific disruption of Cathepsin K protects against doxorubicin-induced cardiotoxicity" @default.
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• W2806003462 doi "https://doi.org/10.1038/s41419-018-0727-2" @default.
• W2806003462 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6895075" @default.
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• W2806003462 hasPublicationYear "2018" @default.
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