GUCY1A1-LDHA Axis Suppresses Ferroptosis in Cardiac Ischemia-Reperfusion Injury

作者：Ming Yin, Li Su, Muyin Liu, Wentao Zhu, Yuqiong Chen, Wenyan Qiu, Qiyu Li, Youran Li, Jinxiang Chen, You Zhou, Danbo Lu, Chenguang Li, Zhangwei Chen, Juying Qian, Junbo Ge · 发表于：Circulation Research · 年份：2025 · DOI：10.1161/circresaha.124.326029 · 被引用次数：18 · 研究领域：Ferroptosis and cancer prognosis、Immune cells in cancer、Cancer-related molecular mechanisms research

BACKGROUND: Ischemia-reperfusion injury compromises revascularization strategies for myocardial infarction and contributes to cardiac microvascular disorders. This study aimed to investigate the role of the sGC (soluble guanylate cyclase)-cGMP (cyclic guanosine monophosphate)-PKG (protein kinase G) pathway in cardiac microvascular reperfusion injury with a focus on ferroptosis. METHODS: /-CreERT2) and adeno-associated virus transfer-induced EC-specific GUCY1A1-overexpressing mice were assessed for cardiac microvascular reperfusion injury. LDHA (lactate dehydrogenase A) and GPX4 (glutathione peroxidase 4) phosphorylation sites were identified by mass spectrometry and mutationally inactivated via the CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and their associated protein 9) system. Protein interactions and chaperone-mediated autophagy of GPX4 were detected using coimmunoprecipitation assays. RESULTS: GUCY1A1 was decreased in the EC group after cardiac ischemia-reperfusion injury. EC-specific knockout of GUCY1A1 further reduced microvascular perfusion, increased the no-reflow area, and enlarged the infarction area in the acute phase of ischemia-reperfusion injury, ultimately aggravating cardiac dysfunction and structural remodeling in the chronic phase. In contrast, GUCY1A1 overexpression or its activator, vericiguat, alleviated microvascular dysfunction via the suppression of endothelial ferroptosis; the effects were majorly dependent on PKG activity...