Abstract 16698: Cardiomyocyte-specific Deletion of Cathepsin K Protects Against Doxorubicin-induced Cardiac Dysfunction
Background and objective: The cysteine protease cathepsin K is elevated in both human and animal models of heart failure. Global deletion of cathepsin K attenuates both high fat diet- and pressure overload-induced cardiac hypertrophy and contractile dysfunction, although the role of cardiac cathepsin K remains unclear. To this end, the objective of this study was to generate a cardiomyocyte-specific knockout of cathepsin K (Ctsk-/-) and to test the hypothesis that deletion of cardiac cathepsin K protects against doxorubicin-induced cardiotoxicity.
Methods: Ctsk-/- mice were generated by Ctsk targeted trap-allele including both FLP-FRT and Cre-lox systems. Cre-recombinase in myosin-heavy chain-Cre transgenic mice recognizes LoxP sites in “floxed (flanked by LoxP)” mice, and deletes the exons from 2 to 5 of Ctsk. Protein and mRNA levels of Ctsk and exon 2 were determined by Western blot and quantitative RT-PCR respectively. Four-months-old control (fl/fl-Cre-) and Ctsk-/- (fl/fl-Cre+) mice received two injections of doxorubicin (10mg/kg, i.p. at 3-day intervals, 20mg/kg cumulative), one week following which, body and tissue weight, echocardiographic properties, cardiomyocyte contractile function and Ca2+-handling were evaluated.
Results: Cathepsin K mRNA and protein were attenuated by over 80% in the hearts of the knockout mice compared to the control. Doxorubicin injections resulted in an increase in total heart mass and the length of individual cardiomyocytes. Furthermore, doxorubicin-treated mice exhibited cardiomyocyte contractile dysfunction, characterized by depressed peak-shortening, maximal velocity of shortening and re-lengthening, and impaired intracellular Ca2+ homeostasis. Additionally, mice receiving doxorubicin exhibited significant increases in end-systolic and end-diastolic diameters and decreased fractional shortening and wall thickness. These deleterious cardiac effects of doxorubicin were significantly attenuated or reversed in mice lacking cardiac cathepsin K.
Conclusion: Mitigation of doxorubicin-induced cardiac anomalies by targeted deletion of cardiac cathepsin K suggests that cathepsin K represents a novel, bona-fide, pharmacological target for cardiac toxicity and complications.
Author Disclosures: R. Guo: None. Y. Hua: None. J. Ren: None. K.E. Bornfeldt: None. S. Nair: None.
- © 2016 by American Heart Association, Inc.