9-磷脂酰高丝氨酸通过促进LKB1/AMPK/ULK1介导的自噬依赖性STING降解来改善心脏缺血/再灌注损伤期间的微血管损伤。
9-PAHSA ameliorates microvascular damage during cardiac ischaemia/reperfusion injury by promoting LKB1/AMPK/ULK1-mediated autophagy-dependent STING degradation.
作者信息
Liu Wenhu, Hu Jing, Wang Ya, Gan Ting, Ding Yan, Wang Xuehua, Xu Qian, Xiong Jingjie, Xiong Ni, Lu Shuai, Wang Yan, Wang Zhaohui
机构信息
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, China.
出版信息
Phytomedicine. 2025 Jan;136:156241. doi: 10.1016/j.phymed.2024.156241. Epub 2024 Nov 17.
BACKGROUND
Considering that cardiac microvascular injury may play a more critical role than cardiomyocyte injury in the pathology of early ischaemia/reperfusion (I/R) injury, therapeutic strategies targeting the microvasculature are highly desirable. Palmitic acid-9-hydroxystearic acid (9-PAHSA) is a new class of bioactive anti-inflammatory lipids widely distributed in vegetables, fruits and medicinal plants, especially broccoli and apple. However, the pharmacological effects and underlying mechanisms of 9-PAHSA in protecting- against cardiac microvascular I/R injury have rarely been studied.
PURPOSE
This study aimed to explore the potential effects and molecular mechanisms of 9-PAHSA on the coronary microvasculature after cardiac I/R injury.
METHODS
Immunofluorescence staining, western blotting, and other experimental methods were used to evaluate the role and mechanism of 9-PAHSA in cardiac microvascular I/R injury in vivo and in vitro.
RESULTS
9-PAHSA administration significantly attenuated myocardial I/R-induced microvascular damage, as indicated by an impaired microvascular structure, reduced regional blood perfusion and decreased endothelial barrier function. In addition, 9-PAHSA administration protected the structure and function of coronary artery endothelial cells (CMECs) to resist I/R damage, an effect that was at least partially mediated by increased autophagy. Mechanistically, 9-PAHSA activated autophagy through the LKB1/AMPK/ULK1 pathway and promoted STING degradation via the autophagic‒lysosomal pathway.
CONCLUSIONS
To our best knowledge, this study is the first to report that 9-PAHSA attenuates cardiac microvascular I/R injury, potentially by activating LKB1/AMPK/ULK1-mediated autophagy-dependent STING degradation to suppress apoptosis. Thus, 9-PAHSA may be a promising therapeutic option for alleviating cardiac microvascular I/R injury.
背景
鉴于心脏微血管损伤在早期缺血/再灌注（I/R）损伤的病理过程中可能比心肌细胞损伤发挥更关键的作用，靶向微血管的治疗策略非常必要。棕榈酸-9-羟基硬脂酸（9-PAHSA）是一类新型生物活性抗炎脂质，广泛分布于蔬菜、水果和药用植物中，尤其是西兰花和苹果。然而，9-PAHSA在预防心脏微血管I/R损伤方面的药理作用和潜在机制鲜有研究。
目的
本研究旨在探讨9-PAHSA对心脏I/R损伤后冠状动脉微血管的潜在作用及其分子机制。
方法
采用免疫荧光染色、蛋白质印迹法等实验方法，在体内和体外评估9-PAHSA在心脏微血管I/R损伤中的作用及机制。
结果
给予9-PAHSA可显著减轻心肌I/R诱导的微血管损伤，表现为微血管结构受损、局部血流灌注减少和内皮屏障功能降低。此外，给予9-PAHSA可保护冠状动脉内皮细胞（CMECs）的结构和功能，使其抵抗I/R损伤，这一作用至少部分是通过增加自噬介导的。机制上，9-PAHSA通过LKB1/AMPK/ULK1途径激活自噬，并通过自噬-溶酶体途径促进STING降解。
结论
据我们所知，本研究首次报道9-PAHSA可减轻心脏微血管I/R损伤，其潜在机制可能是通过激活LKB1/AMPK/ULK1介导的自噬依赖性STING降解来抑制细胞凋亡。因此，9-PAHSA可能是缓解心脏微血管I/R损伤的一种有前景的治疗选择。
Zotero 插件