The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor
Open Access
- 17 April 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Advances
- Vol. 6 (16), eaax4826
- https://doi.org/10.1126/sciadv.aax4826
Abstract
Pathological cardiac hypertrophy leads to heart failure (HF). The ubiquitin-proteasome system (UPS) plays a key role in maintaining protein homeostasis and cardiac function. However, research on the role of deubiquitinating enzymes (DUBs) in cardiac function is limited. Here, we observed that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) was significantly up-regulated in agonist-stimulated primary cardiomyocytes and in hypertrophic and failing hearts. Knockdown of UCHL1 in cardiomyocytes and mouse hearts significantly ameliorated cardiac hypertrophy induced by agonist or pressure overload. Conversely, overexpression of UCHL1 had the opposite effect in cardiomyocytes and rAAV9-UCHL1–treated mice. Mechanistically, UCHL1 bound, deubiquitinated, and stabilized epidermal growth factor receptor (EGFR) and activated its downstream mediators. Systemic administration of the UCHL1 inhibitor LDN-57444 significantly reversed cardiac hypertrophy and remodeling. These findings suggest that UCHL1 positively regulates cardiac hypertrophy by stabilizing EGFR and identify UCHL1 as a target for hypertrophic therapy.Funding Information
- National Natural Science Foundation of China (31571170)
- National Natural Science Foundation of China (81630009)
- National Natural Science Foundation of China (81330003)
- National Natural Science Foundation of China (81700350)
- Chang Jiang Scholar Program of China (T2011160)
- Dalian high-level Talents Innovation and Entrepreneurship Projects (2015R019)
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