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1 Cardiovascular Research Institute, University of South Dakota, Sioux Falls, SD, USA
2 Cardiovascular Research Institute, University of South Dakota, Sioux Falls, SD, USA; Department of Pathophysiology, Guangzhou Medical College, Guangzhou, Guangdong, China
3 Cardiovascular Research Institute, University of South Dakota, Sioux Falls, SD, USA; Department of Pathophysiology, Wuhan University, Wuhan, Hubei, China
4 Cardiovascular Research Institute, University of South Dakota, Sioux Falls, SD, USA; Cardiovascular Research Institute, Nanjing Medical University, Nanjing, Jiangsu, China
5 Cardiovascular Research Institute, South Dakota Health Research Foundation, Sioux Falls, SD, USA; Department of Laboratory Medicine and Pathology, University of South Dakota, Sioux Falls, SD, USA
6 Cardiovascular Research Institute, University of South Dakota, Sioux Falls, SD, USA; Cardiovascular Research Institute, South Dakota Health Research Foundation, Sioux Falls, SD, USA
* To whom correspondence should be addressed. E-mail: xwang{at}usd.edu.
The ubiquitin-proteasome system (UPS) is responsible for the turnover of most cellular proteins in eukaryotes. Protein degradation by the UPS serves both quality control and regulatory functions. Proteasome inhibition showed great promise in effectively treating cancer and restenosis. Meanwhile, UPS dysfunction in cardiac hypertrophy and failure has recently been suspected but remains to be investigated. A system capable of monitoring the dynamic changes in proteolytic function of the UPS in cardiomyocytes in situ would no doubt benefit significantly the efforts to decipher the pathogenic significance of UPS dysfunction in the heart and to evaluate the effect of proteasome inhibition on cardiomyocytes. We have recently successfully established such a system in cultured cardiomyocytes by delivering and expressing a modified green fluorescence protein (GFPu) gene using recombinant adenoviruses. GFPu contains a carboxyl fusion of a ubiquitination signal sequence. Both fluorescence microscopy and western blots revealed that abundance of GFPu but not wild type GFP protein in cultured cardiomyocytes was incrementally increased when function of the proteasomes was inhibited in various degrees by specific inhibitors. The increase in GFPu protein levels and fluorescence intensity is paralleled by a decrease in the in vitro peptidase activity of the proteasomes. Our results demonstrate that GFPu can be used as a surrogate marker to monitor dynamic changes in the proteolytic function of the UPS in cardiomyocytes in situ. Application of this novel system reveals that moderate levels of hydrogen peroxide, a reactive oxygen species generator, impair the proteolytic function of the UPS in cultured cardiac myocytes.
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