Cathepsin K knockout alleviates aging‐induced cardiac dysfunction

Aging Cell

Yinan Hua¹  Timothy J. Robinson⁴  Yongtao Cao³  Guo-Ping Shi²  Jun Ren¹ 

[1] Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, College of Health Sciences, Laramie, WY, USA;Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA;Department of Mathematics, Indiana University of Pennsylvania, Indiana, PA, USA;WWAMI Medical Education, College of Health Sciences, University of Wyoming, Laramie, WY, USA

关键词: aging;    apoptosis;    cardiac remodeling;    cathepsin K;    cardiac function;    cardiac hypertrophy;   

DOI  :  10.1111/acel.12276

来源: Wiley

【 摘 要 】

Summary

Aging is a major risk factor for cardiovascular disease. It has previously been shown that protein levels of cathepsin K, a lysosomal cysteine protease, are elevated in the failing heart and that genetic ablation of cathepsin K protects against pressure overload-induced cardiac hypertrophy and contractile dysfunction. Here we test the hypothesis that cathepsin K knockout alleviates age-dependent decline in cardiac function. Cardiac geometry, contractile function, intracellular Ca²⁺ properties, and cardiomyocyte apoptosis were evaluated using echocardiography, fura-2 technique, immunohistochemistry, Western blot and TUNEL staining, respectively. Aged (24-month-old) mice exhibited significant cardiac remodeling (enlarged chamber size, wall thickness, myocyte cross-sectional area, and fibrosis), decreased cardiac contractility, prolonged relengthening along with compromised intracellular Ca²⁺ release compared to young (6-month-old) mice, which were attenuated in the cathepsin K knockout mice. Cellular markers of senescence, including cardiac lipofuscin, p21 and p16, were lower in the aged-cathepsin K knockout mice compared to their wild-type counterpart. Mechanistically, cathepsin K knockout mice attenuated an age-induced increase in cardiomyocyte apoptosis and nuclear translocation of mitochondrial apoptosis-inducing factor (AIF). In cultured H9c2 cells, doxorubicin stimulated premature senescence and apoptosis. Silencing of cathepsin K blocked the doxorubicin-induced translocation of AIF from the mitochondria to the nuclei. Collectively, these results suggest that cathepsin K knockout attenuates age-related decline in cardiac function via suppressing caspase-dependent and caspase-independent apoptosis.

【 授权许可】

CC BY   
© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.