Cathepsin K knockout alleviates aging‐induced cardiac dysfunction

Abstract

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.

Programmed cell death in aging

“…In mice, over-expression of the mitochondrial antioxidant enzyme MnSOD reduced PCD in the aging heart, thereby implicating mitochondrial function and oxidative stress (Kwak et al, 2014). In addition, mutation of mouse cathepsin K reduced AIG translocation and PCD during aging, resulting in improved heart function and implicating both caspase-dependent and caspase-independent mechanisms(Hua et al, 2015). Finally, increasing GDF-11 levels in the aging mouse had a benefit for heart function, indicating a role for altered systemic signaling in heart aging.…”

Myocardial Upregulation of Cathepsin D by Ischemic Heart Disease Promotes Autophagic Flux and Protects Against Cardiac Remodeling and Heart Failure

“…15, 16 Ctsk deficiency also attenuated aging-induced cardiac dysfunction and high fat diet-induced cardiac hypertrophy and malfunction in mice. 17, 18 These studies indicate that the role of different cathepsins in cardiac pathogenesis varies and must be determined individually.…”

Odanacatib Inhibits Resistin-induced Hypertrophic H9c2 Cardiomyoblast Cells Through LKB1/AMPK Pathway

“…Cathepsin K induces cardiac hypertrophy by activating the mTOR signaling pathway. Cathepsin K gene knockout can inhibit the hypertrophy and apoptosis of cardiomyocytes, but does not change the myocardial fibrosis 32 . ODN is an inhibitor of cathepsin K. Through the experiments using ODN to intervene resistin-induced cardiomyocyte hypertrophy, we found that cell surface area, protein synthesis, BNP and β-MHC expression were significantly decreased, while LKB1 and AMPK phosphorylation levels were significantly increased after treatment with ODN and resistin.…”