Cathepsin K-deficiency impairs mouse cardiac function after myocardial infarction

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<.01,7 days post-MI; 4.32 +/- 0.52 vs. 7.60 +/- 0.82, P<.01, 28 days post-MI). At 7 days post-MI, hearts from 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 alpha-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.