Journal Article Epublish
PubMed: 39897023 DOI: 10.7150/ijbs.102251
Downregulation of PGAM2 alleviates angiotensin II-induced cardiac hypertrophy by destabilizing HSP90 and inactivating the mTOR/IKKα signaling pathway.
Int J Biol Sci 21(3):1308-1321
Authors: Ying Li, Wen-Jing Li, Jia-Min Du, Hui-Hui Wu, Si-Yuan Zhou, Min Li, Yue-Yan Li, Shu-Ya Wang, Hui-Yun Wang, Yan Zheng, Qun-Ye Zhang, Li-Ming Li, Fan-Liang Meng, Guo-Hai Su
Affiliations
- Department of Cardiology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China. Research Center for Translational Medicine, Jinan Central Hospital, Shandong University, Jinan, China.
- Department of Cardiology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
- Research Center for Translational Medicine, Jinan Central Hospital, Shandong University, Jinan, China.
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Department of Cardiology, Qilu Hospital, Shandong University, Jinan 250012, China.
- NingboTech University, Ningbo 315000, Zhejiang, China.
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
Abstract
Pathological cardiac hypertrophy is a major contributor to heart failure. The present study aims to elucidate the role and mechanisms of phosphoglycerate mutase 2 (PGAM2) in the pathogenesis of cardiac hypertrophy. PGAM2 expression was increased in both primary neonatal rat ventricular myocytes (NRVMs) and rat models in response to angiotensin II (Ang II). Downregulation of PGAM2 alleviated cardiac hypertrophy. Mechanistically, we found PGAM2 directly interacts with HSP90 through residues 319-323 and 622-629 in the middle and carboxy-terminal domain of HSP90 respectively. This interaction was further enhanced under Ang II stimulation. Additionally, in the presence of PGAM2, it competed with E3 ubiquitin ligase SYVN1 to interact with HSP90, effectively inhibiting the ubiquitination and degradation of HSP90. Therefore, deficiency of PGAM2 results in the downregulation of the HSP90 and its downstream mTOR and client protein IKKα signaling pathway, both of which play crucial roles in the progression of cardiac hypertrophy. , we further confirmed that PGAM2 knockdown alleviated cardiac hypertrophy through downregulation of HSP90 and mTOR/IKKα signaling pathway. Taken together, we first demonstrated that downregulation of PGAM2 alleviates cardiac hypertrophy induced by Ang II, which provides a novel target for the treatment of myocardial hypertrophy and heart failure.
MeSH
Angiotensin Ii, Ubiquitin, Biological Science Disciplines, Heart Failure, Heart, Hypertrophy, Angiotensins, Ubiquitin-Protein Ligases, Down-Regulation