Department

Department: Pharmacy

First Advisor

Dr. Sreejayan Nair

Description

Background: Heart Failure is the leading cause of death in the US and other developed countries. Programmed cell death of the heart cells (or cardiomyocyte apoptosis) plays a critical role in the development of heart failure. Cathepsins are lysosomal prote ases, which have been reported to regulate apoptosis. However, the role of cathepsin K, the most potent lysosomal enzyme in cardiac apoptosis is still under investigation. Methods and Results: Cultured rat cardiomyoblasts (H9c2 cells) were challenged with the pro - oxidant antimycin A in the presence or absence of cathepsin K inhibitor. Active cathepsin K and lysosome were immunolocalized using specific dyes. Cardiomyocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labelin g (TUNEL staining) and apoptosis - related protein levels were detected by Western blot analysis. Treatment of cardiomyocytes with antimycin A (5 μM) elicited the release cathepsin K from lysosome into the cytoplasm and induced as evidenced by an increase in the number of TUNEL - positive cells and alterations in the levels of apoptosis - related proteins (elevated BAX and decreased Bcl - 2 levels), all of which were reconciled by cathepsin K inhibitor. Conclusions and discussion: Cathepsin K has a permissive role in oxidative stress - induced cardiomyocyte apoptosis. Inhibition of cathepsin K alleviates oxidative stress - induced cardiomyocyte apoptosis, which might represent a strategy for the treatment of a variety of cardiovascular diseases.

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Cathepsin K Inhibition Al leviates Antimycin - Induced Cardiomyocyte Apoptosis

Background: Heart Failure is the leading cause of death in the US and other developed countries. Programmed cell death of the heart cells (or cardiomyocyte apoptosis) plays a critical role in the development of heart failure. Cathepsins are lysosomal prote ases, which have been reported to regulate apoptosis. However, the role of cathepsin K, the most potent lysosomal enzyme in cardiac apoptosis is still under investigation. Methods and Results: Cultured rat cardiomyoblasts (H9c2 cells) were challenged with the pro - oxidant antimycin A in the presence or absence of cathepsin K inhibitor. Active cathepsin K and lysosome were immunolocalized using specific dyes. Cardiomyocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labelin g (TUNEL staining) and apoptosis - related protein levels were detected by Western blot analysis. Treatment of cardiomyocytes with antimycin A (5 μM) elicited the release cathepsin K from lysosome into the cytoplasm and induced as evidenced by an increase in the number of TUNEL - positive cells and alterations in the levels of apoptosis - related proteins (elevated BAX and decreased Bcl - 2 levels), all of which were reconciled by cathepsin K inhibitor. Conclusions and discussion: Cathepsin K has a permissive role in oxidative stress - induced cardiomyocyte apoptosis. Inhibition of cathepsin K alleviates oxidative stress - induced cardiomyocyte apoptosis, which might represent a strategy for the treatment of a variety of cardiovascular diseases.