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CircCHSY1 protects hearts against ischaemia/reperfusion injury by enhancing heme oxygenase 1 expression via miR-24-3p
Jiliang Tan1, Jie Min2, Yun Jiang1
1CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, 320 Yue Yang Road, Shanghai 200031, P.R. China.
Insights
Circular RNA circCHSY1 is upregulated in myocardial ischemia and protects heart cells by enhancing HO1 levels via miR-24-3p, preserving mitochondrial function.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Epigenetics
Background:
- Circular RNAs (circRNAs) play roles in physiological and pathological processes.
- The function of circRNAs, including circCHSY1, in myocardial ischemia-reperfusion (I/R) injury is largely unknown.
- circCHSY1 expression is altered following myocardial I/R injury.
Purpose of the Study:
- To investigate the role of circCHSY1 in acute myocardial I/R injury.
- To elucidate the mechanisms underlying circCHSY1's function in myocardial I/R injury.
Main Methods:
- Detected circCHSY1 expression in mouse, rat, and human embryonic stem cell-derived cardiomyocytes (hESC-CMs).
- Utilized adenovirus-mediated overexpression and siRNA-mediated knockdown of circCHSY1 in I/R and oxygen-glucose deprivation/reperfusion (OGD/R) models.
- Investigated molecular mechanisms using dual-luciferase assays, RNA pull-down assays, and Western blotting.
- Assessed infarct size, lactate dehydrogenase (LDH) release, cell viability, and mitochondrial function.
Main Results:
- circCHSY1 expression was upregulated in I/R and OGD/R models.
- Overexpression of circCHSY1 reduced infarct size and LDH release, improved cell viability, and preserved mitochondrial function in I/R and OGD/R models.
- circCHSY1 interacted with miR-24-3p, which targets heme oxygenase 1 (HO1).
- circCHSY1 overexpression enhanced HO1 levels, and HO1 knockdown abolished the protective effects of circCHSY1.
Conclusions:
- circCHSY1 is upregulated in myocardial I/R injury and exerts a protective effect.
- circCHSY1 protects against myocardial I/R injury by enhancing HO1 levels via targeting miR-24-3p, thereby preserving mitochondrial homeostasis.
- circCHSY1 is identified as a potential protective factor against myocardial I/R injury.
Aims:
Circular RNAs (circRNAs) are important players involved in a variety of physiological and pathological processes. However, their functions and mechanisms during myocardial ischaemic injury and protection remain largely unknown. We recently found significant alterations of many circRNAs including circCHSY1 following myocardial ischaemia/reperfusion (I/R) injury, whereas their exact functions are unclear. Here, we investigated the roles of circCHSY1 in the acute myocardial I/R injury and the potential mechanisms involved.
Methods And Results:
The expression of circCHSY1 was detected in cardiomyocytes from mouse, rat, and human embryonic stem cells (hESC-CMs). It was further up-regulated in mouse I/R (30 min/24 h) hearts, oxygen glucose deprivation/reperfusion (OGD/R, 6 h/2 h) primary neonatal rat ventricular cardiomyocytes (NRCMs) and OGD/R (48 h/2 h) hESC-CMs. Adenovirus-mediated circCHSY1 overexpression significantly decreased infarct size and lactate dehydrogenase (LDH) release in mouse I/R hearts. Consistently, circCHSY1 overexpression reduced the LDH release in the OGD/R NRCMs and hESC-CMs, improved cell viability, and preserved mitochondrial function in the OGD/R NRCMs, whereas there were no significant differences in cell viability and LDH release between the OGD/R NRCMs with and without small interfering RNA (siRNA)-mediated circCHSY1 knockdown. Mechanistically, circCHSY1 was detected to bind with miR-24-3p analysed by dual-luciferase assay and RNA pull-down assays. CircCHSY1 overexpression-mediated protective effects on cells and mitochondria in OGD/R NRCMs were reversed by the miR-24-3p mimic. Furthermore, dual-luciferase assay showed that miR-24-3p was directly bound to heme oxygenase 1 (HO1) via its 3'UTR. The protein level of HO1 was down-regulated by miR-24-3p mimic in OGD/R NRCMs but enhanced by the circCHSY1 overexpression in vitro and in vivo. Functionally, the HO1 knockdown by adenovirus in vivo and by siRNA in vitro eliminated cardioprotective effects of circCHSY1 overexpression.
Conclusion:
CircCHSY1 is up-regulated following myocardial I/R injury. The higher level of circCHSY1 protects I/R hearts and cardiomyocytes. The protection of circCHSY1 is mediated through enhancement of the HO1 level, resulting in preserving mitochondrial homoeostasis via targeting miR-24-3p in cardiomyocytes. These findings suggest circCHSY1 as a protective factor.
