Published online before print October 6, 2005, doi: 10.1161/01.RES.0000189262.92896.0b
© 2005 American Heart Association, Inc.
Cellular Biology |
Intrasarcoplasmic Amyloidosis Impairs Proteolytic Function of Proteasomes in Cardiomyocytes by Compromising Substrate Uptake
From the Cardiovascular Research Institute (Q.C., J.-B.L., K.M.H., H.Z., A.R.K.K., J.L., F.L., A.M.G., X.W.), South Dakota Health Research Foundation, University of South Dakota School of Medicine and Sioux Valley Hospitals and Health System, Sioux Falls; National Eye Institute (E.F.W.), National Institutes of Health, Bethesda, Md; Department of Pathophysiology (J.-B. L), Guangzhou Medical College, Guangzhou, Guangdong, China; and Department of Laboratory Medicine (F. L.) and Division of Basic Biomedical Sciences (Q.C., J.-B.L., K.M.H., H.Z., A.R.K.K., J.L., X.W.), University of South Dakota School of Medicine, Sioux Falls.
Correspondence to Xuejun Wang, MD, PhD, Cardiovascular Research Institute, University of South Dakota School of Medicine, 1100 E 21st St, Ste 700, Sioux Falls, SD 57105. E-mail xwang{at}usd.edu
The presence of increased ubiquitinated proteins and amyloid oligomers in failing human hearts strikingly resembles the characteristic pathology in the brain of many neurodegenerative diseases. The ubiquitin–proteasome system (UPS) is responsible for degradation of most cellular proteins and plays essential roles in virtually all cellular processes. UPS impairment by aberrant protein aggregation was previously shown in cell culture but remains to be demonstrated in intact animals. Mechanisms underlying the impairment are poorly understood. We report here that UPS proteolytic function is severely impaired in the heart of a mouse model of intrasarcoplasmic amyloidosis caused by cardiac-restricted expression of a human desmin–related myopathy-linked missense mutation of 
B-crystallin (CryABR120G). The UPS impairment was detected before cardiac hypertrophy, and failure became discernible, suggesting that defective protein turnover likely contributes to cardiac remodeling and failure in this model. Further analyses reveal that the impairment is likely attributable to insufficient delivery of substrate proteins into the 20S proteasomes, and depletion of key components of the 19S subcomplex may be responsible. The derangement is likely caused by aberrant protein aggregation rather than loss of function of the CryAB gene because UPS malfunction was not evident in CryAB-null hearts and inhibition of aberrant protein aggregation by Congo red or a heat shock protein significantly attenuated CryABR120G-induced UPS malfunction in cultured cardiomyocytes. Because of the central role of the UPS in cell regulation and the high intrasarcoplasmic amyloidosis prevalence in failing human hearts, our data suggest a novel pathogenic process in cardiac disorders with abnormal protein aggregation.
Key Words: proteasome • ubiquitin • protein aggregation • B-crystallin • desmin-related cardiomyopathy • amyloidosis • transgenic mice
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