A research team led by Prof. YANG Huangtian from the Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences, in collaboration with Prof. WANG Zhinong from the Shanghai Changzheng Hospital, Naval Medical University, identified novel functions of a circular RNA (circRNA) CircCHSY1 in protecting hearts against ischemia/reperfusion (I/R) injury via maintenance of mitochondrial homeostasis. The work entitled "CircCHSY1 protects hearts against ischemia/reperfusion injury by enhancing heme oxygenase 1 expression via miR-24-3p" was published online in Cardiovascular Research on July, 31, 2024.  

Restoration of blood supply timely after myocardial infarction is essential to save the ischemic heart. However, it is accompanied by reperfusion injury, termed myocardial I/R injury. Currently, the existing interventions available clinically are very limited. Therefore, it is of great scientific significance and clinical demand to find new mechanisms to reduce I/R injury.

CircRNAs, a class of covalently closed single-stranded ncRNAs, form via backsplicing of exons or/and introns. Their important roles in human physiological and pathological processes have been documented. However, little is known about roles of circRNAs in myocardial I/R injury. During myocardial I/R injury, mitochondria play a decisive role in cell survival, highlighting the importance of maintaining mitochondrial homeostasis in protecting the heart against I/R injury. However, whether circRNAs are involved in the regulation of mitochondrial homeostasis during I/R remains unknown.

Based on the RNA-seq screening data, the researchers from SINH and collaborators identified a circRNA circCHSY1 is upregulated during myocardial I/R injury. Further analysis showed that increased expression of circCHSY1 effectively protected the hearts and cardiomyocytes against I/R injury in mouse in vivo model and rat cardiomyocytes model which subjected to a glucose deprivation/reperfusion (OGD/R) injury. Overexpression of circCHSY1 maintained mitochondrial homeostasis in the cardiomyocytes and attenuated the cardiomyocyte OGD/R injury.

Through bioinformatics analysis, molecular and cellular experiments, the researchers identified miR-24-3p as the binding target of circCHSY1, and circCHSY1 overexpression-mediated protective effects on cells and mitochondria were reversed by the miR-24-3p mimic. Moreover, miR-24-3p downregulated the expression of heme oxygenase 1 (HO1) protein, a mitochondrial regulatory protein, via directly binding to HO1, but it was reversed by overexpression of circCHSY1 in OGD/R cardiomyocytes and myocardial I/R injury model. Functionally, HO1 knockdown eliminated cardioprotective effects of circCHSY1 overexpression. Furthermore, the researchers validated the protective role of circCHSY1 in the OGD/R model of human embryonic stem cell-derived cardiomyocytes.

In summary, CircCHSY1 is upregulated following myocardial I/R injury. The higher level of circCHSY1 protects I/R hearts and cardiomyocyte through enhancement of the HO1 level, resulting in preserving mitochondrial homeostasis via targeting miR-24-3p in cardiomyocytes. These findings suggest that circCHSY1 might act as an endogenous protective factor and provide novel therapeutic insights into circRNA-regulated pathways against myocardial I/R injury.

This work was funded by the grant from National Natural Science Foundation of China.

 The protective effect of circCHSY1 on myocardial I/R injury (Image provided by Prof. YNAG Huangtian's team)

Media Contact:
WANG Jin
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: wangjin01@sinh.ac.cn
Web: http://english.sinh.cas.cn/