Abstract 13630: Cathepsin K Knockout Mitigates High Fat Diet-Induced Cardiac Dysfunction
Cathepsin K (catK) is a lysosomal cysteine proteinase with elastolytic and collagenolytic activities. Recent studies have implicated a role of catK in obesity associated-insulin resistance. However, the role of catK in diabetic cardiomyopathy is still unknown. The aim of this study was to test the hypothesis that catK knock-out (CatK−/−) protects against a high fat diet (HFD)-induced cardiac dysfunction. Cardiac functions were evaluated in wild type (WT) and CatK−/− mice fed with a normal diet or a HFD for 5 months. HFD consumption resulted in elevated body weight, heart weight (HW) as well as HW-to-tibia length ratio in WT mice, all of which were attenuated in CatK−/− mice. Intraperitoneal glucose tolerance test demonstrated a significant insulin resistance in HFD-fed WT mice, which was alleviated in CatK−/− mice. Echocardiography showed an increase in wall thickness and decrease in fractional shortening following HFD which were partially reconciled in CatK−/− mice. Single myocyte contractility assessed as peak-shortening, maximal velocity of shortening and relengthening was impaired following HFD and was partially restored in CatK−/− mice. H&E staining revealed that HFD-fed WT mice had larger cardiomyocytes, significantly larger than those in CatK−/− mice. HFD-feeding resulted in extensive mitochondrial injury and reactive oxygen species (ROS) production in isolated cardiomyocytes as assessed by transmission electron microscopy and dichlorofluorescein assay respectively, both of which were unchanged in CatK−/− mice. Cardiac cytochrome C, BAX, cleaved-caspase 3, and cleaved-PARP were elevated in HFD-fed mice which was attenuated by CatK−/−. In H9c2 myoblasts, siRNA mediated silencing of catK inhibited apoptosis induced by palmitic acid (PA). Dual immunostaining for lysosome and catK indicated that treatment with PA caused release of catK from the lysosomes into the cytoplasm. We conclude from the present study that catK plays an important role in obesity-induced cardiac dysfunction. CatK may inhibit the apoptotic pathway triggered by mitochondrial damage and ROS as a consequence of HFD. CatK inhibition may thus represent a strategy for the treatment to diabetic cardiomyopathy.
- © 2011 by American Heart Association, Inc.