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Inadequate ubiquitination-proteasome coupling contributes to myocardial ischemia-reperfusion injury
Chengjun Hu, … , Jinbao Liu, Xuejun Wang
Chengjun Hu, … , Jinbao Liu, Xuejun Wang
Published September 11, 2018
Citation Information: J Clin Invest. 2018;128(12):5294-5306. https://doi.org/10.1172/JCI98287.
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Research Article Cardiology

Inadequate ubiquitination-proteasome coupling contributes to myocardial ischemia-reperfusion injury

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Abstract

The ubiquitin-proteasome system (UPS) degrades a protein molecule via 2 main steps: ubiquitination and proteasomal degradation. Extraproteasomal ubiquitin receptors are thought to couple the 2 steps, but this proposition has not been tested in vivo with vertebrates. More importantly, impaired UPS performance plays a major role in cardiac pathogenesis, including myocardial ischemia-reperfusion injury (IRI), but the molecular basis of UPS impairment remains poorly understood. Ubiquilin1 is a bona fide extraproteasomal ubiquitin receptor. Here, we report that mice with a cardiomyocyte-restricted knockout of Ubiquilin1 (Ubqln1-CKO mice) accumulated a surrogate UPS substrate (GFPdgn) and increased myocardial ubiquitinated proteins without altering proteasome activities, resulting in late-onset cardiomyopathy and a markedly shortened life span. When subject to regional myocardial ischemia-reperfusion, young Ubqln1-CKO mice showed substantially exacerbated cardiac malfunction and enlarged infarct size, and conversely, mice with transgenic Ubqln1 overexpression displayed attenuated IRI. Furthermore, Ubqln1 overexpression facilitated proteasomal degradation of oxidized proteins and the degradation of a UPS surrogate substrate in cultured cardiomyocytes without increasing autophagic flux. These findings demonstrate that Ubiquilin1 is essential to cardiac ubiquitination-proteasome coupling and that an inadequacy in the coupling represents a major pathogenic factor for myocardial IRI; therefore, strategies to strengthen coupling have the potential to reduce IRI.

Authors

Chengjun Hu, Yihao Tian, Hongxin Xu, Bo Pan, Erin M. Terpstra, Penglong Wu, Hongmin Wang, Faqian Li, Jinbao Liu, Xuejun Wang

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Figure 8

Tg Ubqln1 overexpression reduces infarct size during acute myocardial IRI in mice.

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Tg Ubqln1 overexpression reduces infarct size during acute myocardial IR...
(A–C) The induction of myocardial IRI in Ubqln1-Tg and nTg littermate mice and the subsequent processing and measurements at the terminal experiment were performed in the same way as described for Figures 5 and 6. Two-tailed Student’s t test. Each dot represents an individual animal. Scale bars = 5 mm.
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