BEYOND SLICING AND DICING: CYSTEINE PROTEASE CATHEPSIN K A NOVEL TARGET FOR CARDIOMETABOLIC DISEASE



Sreejayan Nair, Ph.D., University of Wyoming, Laramie, WY, USA

Cathepsin K is a lysosomal cysteine protease with potent collagenolytic and elastolytic properties. Elevated levels of cathepsin K have been reported in both human and animal models of heart failure. Studies from our lab have demonstrated that global deletion of cathepsin K attenuates cardiac hypertrophy and contractile dysfunction in a variety of animal models of cardiac dysfunction including high-fat diet feeding, pressure overload, diabetic cardiomyopathy, alcoholic cardiomyopathy and ageing. Recently we have generated a cardiomyocyte-specific knockout of cathepsin K using the Cre-Lox system and found that this knockout protects mice against doxorubicin-induced cardiotoxicity. Cathepsin K knockout alleviates hyperglycemia and improves whole-body glucose disposal in both streptozotocin-induced and obesity associated diabetic mice. At the molecular level, cathepsin K knockout attenuated oxidative stress and inhibited mitochondrial apoptosis and attenuated oxidative stress. Excessive oxidative stress associated with cardiac pathology results in impairment of lysosomal membrane stability that causes the release of cathepsin K into the cytoplasm where it triggers mitochondrial apoptosis. Cathepsin K knockout also augmented autophagic flux and inhibited calcineurin/NFATc signaling. The molecular studies suggest that cathepsin K may be playing a nontraditional role in the context of the pathophysiology of cardiovascular disease. Cathepsin K thus represents a novel, bona-fide, pharmacological target for treating cardiometabolic complications.