Zhang Hao, Xu Tianyu, Mei Xiyuan, Zhao Qiming, Yang Qiling, Zeng Xianghui, Ma Zhuang, Zhou Haobin, Zeng Qingchun, Xu Dingli, Ren Hao
State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Key Laboratory For Organ Failure Research, Ministry of Education of the People's Republic of China, Guangzhou, China.
Clin Transl Med. 2025 Jan;15(1):e70166. doi: 10.1002/ctm2.70166.
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.
This study aimed to investigate the interaction between PINK1 and Prdx2 to mitigate cardiac diastolic dysfunction in HFpEF.
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.
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) pathways, whereas siRNA-mediated Prdx2 knockdown abolished the protective effect of PINK1.
PINK1 alleviates lipotoxicity-induced myocardial apoptosis and improves diastolic dysfunction in HFpEF through Prdx2, highlighting PINK1 overexpression as a potential therapeutic strategy for HFpEF.
Our investigation discloses a pivotal relationship between PINK1 and Prdx2 in the context of HFpEF. Notably, PINK1, in addition to its role in mitochondrial autophagy, can increase Prdx2 expression, effectively remove ROS and attenuate cardiomyocyte apoptosis by modulating the JNK and p38 pathways, thereby alleviating myocardial lipotoxicity and improving HFpEF cardiac function. Our studies offer valuable insights, opening avenues for the development of innovative therapeutic strategies in the prevention and treatment of HFpEF.
射血分数保留的心力衰竭（HFpEF）是一种复杂的病症，其特征为代谢功能障碍和心肌脂毒性。PTEN诱导激酶1（PINK1）和过氧化物酶体增殖物激活受体γ辅激活因子2（Prdx2）在HFpEF发病机制中的作用仍不清楚。
本研究旨在探究PINK1与Prdx2之间的相互作用，以减轻HFpEF中的心脏舒张功能障碍。
在体内，利用PINK1基因敲除小鼠和心脏特异性PINK1过表达转基因小鼠，通过高脂饮食和L-精氨酸甲酯（L-NAME）建立HFpEF小鼠模型。在体外，用棕榈酸诱导心肌脂毒性。进行免疫沉淀、蛋白质印迹和免疫荧光分析以阐明其中涉及的分子机制。
我们确定在HFpEF小鼠模型中PINK1和Prdx2表达下调。在体内，PINK1基因敲除加剧了Prdx2表达的降低，使HFpEF小鼠的心脏功能障碍恶化。相反，PINK1过表达恢复了Prdx2水平，降低了活性氧水平和细胞凋亡，从而减少纤维化和炎症，并改善了HFpEF小鼠的心脏舒张功能障碍。在体外，鉴定出PINK1的N端区域（氨基酸1-133）与Prdx2之间存在相互作用。PINK1过表达诱导Prdx2表达，并通过c-Jun氨基末端激酶（JNK）和丝裂原活化蛋白激酶（p38）途径有效减轻棕榈酸诱导的细胞凋亡，而小干扰RNA（siRNA）介导的Prdx2敲低消除了PINK1的保护作用。
PINK1通过Prdx2减轻脂毒性诱导的心肌细胞凋亡并改善HFpEF中的舒张功能障碍，突出了PINK1过表达作为HFpEF潜在治疗策略的作用。
我们的研究揭示了在HFpEF背景下PINK1与Prdx2之间的关键关系。值得注意的是，PINK1除了在线粒体自噬中的作用外，还可通过调节JNK和p38途径增加Prdx2表达，有效清除活性氧并减轻心肌细胞凋亡，从而减轻心肌脂毒性并改善HFpEF心脏功能。我们的研究提供了有价值的见解为开发预防和治疗HFpEF的创新治疗策略开辟了道路。
