9-PAHSA ameliorates microvascular damage during cardiac ischaemia/reperfusion injury by promoting LKB1/AMPK/ULK1-mediated autophagy-dependent STING degradation

Wenhu Liu; Jing Hu; Ya Wang; Ting Gan; Yan Ding; Xuehua Wang; Qian Xu; Jingjie Xiong; Ni Xiong; Shuai Lu; Yan Wang; Zhaohui Wang

doi:10.1016/j.phymed.2024.156241

9-PAHSA ameliorates microvascular damage during cardiac ischaemia/reperfusion injury by promoting LKB1/AMPK/ULK1-mediated autophagy-dependent STING degradation

Phytomedicine. 2024 Nov 17:136:156241. doi: 10.1016/j.phymed.2024.156241. Online ahead of print.

Authors

Wenhu Liu¹, Jing Hu², Ya Wang¹, Ting Gan¹, Yan Ding¹, Xuehua Wang¹, Qian Xu¹, Jingjie Xiong¹, Ni Xiong¹, Shuai Lu¹, Yan Wang³, Zhaohui Wang⁴

Affiliations

¹ 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.
² 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.
³ 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. Electronic address: tomato82@126.com.
⁴ 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. Electronic address: wuxiaohongtian@163.com.

PMID: 39579609
DOI: 10.1016/j.phymed.2024.156241

Abstract

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.

Keywords: 9-PAHSA; AMPK/ULK1; Autophagy; Cardiac microvascular ischaemia/reperfusion injury; Mitochondrial homeostasis; STING.