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Updated: Apr 17, 2026
Isolation and Physiological Analysis of Mouse Cardiomyocytes
Published on: September 7, 2014
Cathepsin K knockout alleviates aging-induced cardiac dysfunction
Yinan Hua1, Timothy J Robinson, Yongtao Cao
1Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, College of Health Sciences, Laramie, WY, 82071, USA.
Insights
Cathepsin K knockout alleviates age-related cardiac decline by reducing apoptosis and senescence in aging hearts. This genetic intervention preserves cardiac function and structure in aged mice.
Area of Science:
- Cardiovascular Biology
- Aging Research
- Molecular Cardiology
Background:
- Aging is a primary risk factor for cardiovascular disease.
- Elevated cathepsin K levels are observed in failing hearts.
- Genetic deletion of cathepsin K protects against cardiac hypertrophy and dysfunction.
Purpose of the Study:
- To investigate the role of cathepsin K in age-dependent cardiac dysfunction.
- To determine if cathepsin K knockout mitigates age-related cardiac decline.
Main Methods:
- Echocardiography for cardiac geometry and function.
- Fura-2 technique for intracellular Ca(2+) handling.
- Immunohistochemistry, Western blot, and TUNEL staining for apoptosis and senescence markers.
- In vitro studies using H9c2 cells.
Main Results:
- Aged mice showed cardiac remodeling, reduced contractility, and impaired Ca(2+) handling compared to young mice.
- Cathepsin K knockout attenuated age-related cardiac remodeling and functional decline.
- Cathepsin K knockout reduced markers of senescence and cardiomyocyte apoptosis.
- Cathepsin K inhibition blocked mitochondrial apoptosis-inducing factor nuclear translocation.
Conclusions:
- Cathepsin K knockout ameliorates age-associated cardiac dysfunction.
- The protective effect involves suppression of both caspase-dependent and independent apoptosis.
- Targeting cathepsin K may offer a therapeutic strategy for age-related heart disease.
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 Ca(2+) 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 Ca(2+) 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.
