| First Author | Guo R | Year | 2018 |
| Journal | Cell Death Dis | Volume | 9 |
| Issue | 6 | Pages | 692 |
| PubMed ID | 29880809 | Mgi Jnum | J:314812 |
| Mgi Id | MGI:6823079 | Doi | 10.1038/s41419-018-0727-2 |
| Citation | Guo R, et al. (2018) Cardiomyocyte-specific disruption of Cathepsin K protects against doxorubicin-induced cardiotoxicity. Cell Death Dis 9(6):692 |
| abstractText | 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 alpha-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-kappaB signaling and apoptosis to ameliorate doxorubicin-induced cardiotoxicity. Cathepsin K may represent a viable drug target to treat cardiac disease. |
