Cathepsin K-deficiency impairs mouse cardiac function after myocardial infarction

Abstract Background Extracellular matrix metabolism and cardiac cell death participate centrally in myocardial infarction (MI). This study tested the roles of collagenolytic cathepsin K (CatK) in post-MI left ventricular remodeling. Methods and results Patients with acute MI had higher plasma CatK levels (20.49 ± 7.07 pmol/L, n  = 26) than those in subjects with stable angina pectoris (8.34 ± 1.66 pmol/L, n  = 28, P  = .01) or those without coronary heart disease (6.63 ± 0.84 pmol/L, n  = 93, P  = .01). CatK protein expression increases in mouse hearts at 7 and 28 days post-MI. Immunofluorescent staining localized CatK expression in cardiomyocytes, endothelial cells, fibroblasts, macrophages, and CD4 + T cells in infarcted mouse hearts at 7 days post-MI. To probe the direct participation of CatK in MI, we produced experimental MI in CatK-deficient mice ( Ctsk −/− ) and their wild-type ( Ctsk +/+ ) littermates. CatK-deficiency yielded worsened cardiac function at 7 and 28 days post-MI, compared to Ctsk +/+ littermates (fractional shortening percentage: 5.01 ± 0.68 vs. 8.62 ± 1.04, P vs. 7.60 ± 0.82, P Ctsk −/− mice contained less CatK-specific type-I collagen fragments (10.37 ± 1.91 vs. 4.60 ± 0.49 ng/mg tissue extract, P  = .003) and more fibrosis (1.67 ± 0.93 vs. 0.69 ± 0.20 type-III collagen positive area percentage, P  = .01; 14.25 ± 4.12 vs. 6.59 ± 0.79 α-smooth muscle actin-positive area percentage, P  = .016; and 0.82 ± 0.06 vs. 0.31 ± 0.08 CD90-positive area percentage, P  = .008) than those of Ctsk +/+ mice. Immunostaining demonstrated that CatK-deficiency yielded elevated cardiac cell death but reduced cardiac cell proliferation. In vitro studies supported a role of CatK in cardiomyocyte survival. Conclusion Plasma CatK levels are increased in MI patients. Heart CatK expression is also elevated post-MI, but CatK-deficiency impairs post-MI cardiac function in mice by increasing myocardial fibrosis and cardiomyocyte death.