2025-03-07 中国科学院(CAS)
<関連情報>
- https://english.cas.cn/newsroom/research_news/life/202503/t20250310_903415.shtml
- https://www.jmcc-online.com/article/S0022-2828(25)00041-0/abstract
非共役タンパク質3はアスパラギン酸のダウンレギュレーションを介して病的心肥大から保護する Uncoupling protein 3 protects against pathological cardiac hypertrophy via downregulation of aspartate
Yajun Wang∙ Jiliang Tan∙ Luxiao Li∙ … ∙ Huitong Shan ∙ Huiyong Yin∙ Huang-Tian Yang
Journal of Molecular and Cellular Cardiology Published:March 2, 2025
DOI:https://doi.org/10.1016/j.yjmcc.2025.03.001
Graphical abstract
Highlights
- UCP3 is downregulated in hypertrophic hearts and cardiomyocytes.
- UCP3 prevents TAC- and phenylephrine-induced cardiac and cardiomyocyte hypertrophy.
- UCP3 suppresses the increased aspartate and GOT2 activity during cardiac hypertrophy.
- UCP3 prevents cardiomyocyte hypertrophy via downregulation of aspartate.
Abstract
Metabolic remodeling involving alterations in the substrate utilization is a key feature of cardiac hypertrophy. However, the molecular mechanisms underlying regulation of tricarboxylic acid cycle intermediates by mitochondrial membrane proteins during cardiac hypertrophy have not yet been fully clarified. Mitochondrial uncoupling protein 3 (UCP3), an anion transporter located on the inner mitochondrial membrane, exerts cardioprotective effects against ischemia/reperfusion injury and its insufficiency exacerbates left ventricular (LV) diastolic dysfunction during hypertension. However, its role in pressure overload-induced cardiac hypertrophy remains unknown. Here, we found that UCP3 was downregulated in the mouse LV with transverse aortic constriction (TAC)-induced pathological hypertrophy and in phenylephrine (PE)-stimulated hypertrophic neonatal rat cardiomyocytes (NRCMs). The TAC-induced hypertrophy and LV dysfunction were aggravated in global and cardiac specific knockout of UCP3 (UCP3cKO) mice but improved by cardiac specific overexpression of UCP3 (UCP3cOE). Similar alterations in hypertrophy were observed in PE-treated NRCMs with UCP3-knockdown/overexpression. Moreover, the TAC-increased aspartate and glutamic-oxaloacetic transaminase 2 (GOT2) activity were enhanced in UCP3cKO hearts but reversed in UCP3cOE ones. PE-induced increases of GOT2 activity were enhanced in the UCP3-knockdown NRCMs but attenuated in the UCP3 overexpression ones, accompanied with the downregulation of aspartate. The endogenous interaction of UCP3 and GOT2 was weakened in the PE-treated NRCMs compared with the PE-untreated cells. Furthermore, aspartate supplementation reversed the UCP3 overexpression-attenuated hypertrophy in the PE-stimulated NRCMs. In conclusion, UCP3 expression is downregulated in hypertrophic hearts and cardiomyocytes, whereas the increase of UCP3 mitigates cardiac hypertrophy by downregulation of the enhanced aspartate. These findings provide new knowledge for the function of UCP3 and therapeutic target for cardiac hypertrophy.
