PINK1 modulates Prdx2 to reduce lipotoxicity‐induced apoptosis and attenuate cardiac dysfunction in heart failure mice with a preserved ejection fraction

作者：Hao Zhang, Tianyu Xu, Xiyuan Mei, Qiming Zhao, Qiling Yang, Xianghui Zeng, Zhuang Ma, Haobin Zhou, Zeng Qingchun, Dingli Xu, Hao Ren · 发表于：Clinical and Translational Medicine · 年份：2025 · DOI：10.1002/ctm2.70166 · 被引用次数：8 · 研究领域：Cardiac Fibrosis and Remodeling、Redox biology and oxidative stress、Cardiovascular Function and Risk Factors

INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) is a complex condition characterized by metabolic dysfunction and myocardial lipotoxicity. The roles of PTEN-induced kinase 1 (PINK1) and peroxiredoxin-2 (Prdx2) in HFpEF pathogenesis remain unclear. OBJECTIVE: This study aimed to investigate the interaction between PINK1 and Prdx2 to mitigate cardiac diastolic dysfunction in HFpEF. METHODS: In vivo, PINK1-knockout mice and cardiac-specific PINK1-overexpressing transgenic mice were used to establish an HFpEF mouse model via a high-fat diet and L-NAME. Myocardial lipotoxicity was induced by palmitic acid in vitro. Immunoprecipitation, western blotting and immunofluorescence analysis were performed to elucidate the molecular mechanisms involved. RESULTS: We determined that PINK1 and Prdx2 were downregulated in the HFpEF mouse model. In vivo, PINK1 ablation exacerbated the reduction in Prdx2 expression, worsening cardiac dysfunction in HFpEF mice. Conversely, PINK1 overexpression restored Prdx2 levels and decreased reactive oxygen species and apoptosis, thereby reducing fibrosis and inflammation and ameliorating cardiac diastolic dysfunction in HFpEF mice. In vitro, an interaction between the N-terminal region (amino acids 1-133) of PINK1 and Prdx2 was identified. The overexpression of PINK1 induced Prdx2 expression and effectively attenuated palmitic acid-induced apoptosis through the c-Jun amino-terminal kinase (JNK) and mitogen-activated protein kinase (p38)...