| First Author | Li J | Year | 2011 |
| Journal | J Clin Invest | Volume | 121 |
| Issue | 9 | Pages | 3689-700 |
| PubMed ID | 21841311 | Mgi Jnum | J:178249 |
| Mgi Id | MGI:5297758 | Doi | 10.1172/JCI45709 |
| Citation | Li J, et al. (2011) Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice. J Clin Invest 121(9):3689-700 |
| abstractText | The ubiquitin-proteasome system degrades most intracellular proteins, including misfolded proteins. Proteasome functional insufficiency (PFI) has been observed in proteinopathies, such as desmin-related cardiomyopathy, and implicated in many common diseases, including dilated cardiomyopathy and ischemic heart disease. However, the pathogenic role of PFI has not been established. Here we created inducible Tg mice with cardiomyocyte-restricted overexpression of proteasome 28 subunit alpha (CR-PA28alphaOE) to investigate whether upregulation of the 11S proteasome enhances the proteolytic function of the proteasome in mice and, if so, whether the enhancement can rescue a bona fide proteinopathy and protect against ischemia/reperfusion (I/R) injury. We found that CR-PA28alphaOE did not alter the homeostasis of normal proteins and cardiac function, but did facilitate the degradation of a surrogate misfolded protein in the heart. By breeding mice with CR-PA28alphaOE with mice representing a well-established model of desmin-related cardiomyopathy, we demonstrated that CR-PA28alphaOE markedly reduced aberrant protein aggregation. Cardiac hypertrophy was decreased, and the lifespan of the animals was increased. Furthermore, PA28alpha knockdown promoted, whereas PA28alpha overexpression attenuated, accumulation of the mutant protein associated with desmin-related cardiomyopathy in cultured cardiomyocytes. Moreover, CR-PA28alphaOE limited infarct size and prevented postreperfusion cardiac dysfunction in mice with myocardial I/R injury. We therefore conclude that benign enhancement of cardiac proteasome proteolytic function can be achieved by CR-PA28alphaOE and that PFI plays a major pathogenic role in cardiac proteinopathy and myocardial I/R injury. |
