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CircRNA Samd4 induces cardiac repair after myocardial infarction by blocking mitochondria-derived ROS output
Hao Zheng1, Senlin Huang1, Guoquan Wei1
1Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515 Guangzhou, China; Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), 510005 Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, 510515 Guangzhou, China.
Abstract:
Reactive oxygen species (ROS) derived from oxygen-dependent mitochondrial metabolism are the essential drivers of cardiomyocyte (CM) cell-cycle arrest in adulthood. Mitochondria-localized circular RNAs (circRNAs) play important roles in regulating mitochondria-derived ROS production, but their functions in cardiac regeneration are still unknown. Herein, we investigated the functions and underlying mechanism of mitochondria-localized circSamd4 in cardiac regeneration. We found that circSamd4 was selectively expressed in fetal and neonatal CMs. The transcription factor Nrf2 controlled circSamd4 expression by binding to the promoter of circSamd4 host gene. CircSamd4 overexpression reduced while circSamd4 silenced increased mitochondrial oxidative stress and subsequent oxidative DNA damage. Moreover, circSamd4 overexpression induced CM proliferation and prevented CM apoptosis, which reduced the size of the fibrotic area and improved cardiac function after myocardial infarction (MI). Mechanistically, circSamd4 reduced oxidative stress generation and maintained mitochondrial dynamics by inducing the mitochondrial translocation of the Vcp protein, which downregulated Vdac1 expression and prevented the mitochondrial permeability transition pore (mPTP) from opening. Our findings suggest that circSamd4 is a novel therapeutic target for heart failure after MI.
Insights
Mitochondria-localized circular RNA circSamd4 promotes cardiomyocyte proliferation and cardiac repair after heart attack by reducing oxidative stress. This finding reveals circSamd4 as a potential therapeutic target for heart failure.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Biology
- RNA Biology
Background:
- Reactive oxygen species (ROS) from mitochondrial metabolism cause cardiomyocyte cell-cycle arrest in adults.
- Mitochondria-localized circular RNAs (circRNAs) regulate ROS, but their role in cardiac regeneration is unclear.
Purpose of the Study:
- Investigate the function and mechanism of mitochondria-localized circSamd4 in cardiac regeneration.
- Determine circSamd4's role in regulating cardiomyocyte proliferation and survival post-myocardial infarction (MI).
Main Methods:
- Assessed circSamd4 expression in cardiomyocytes (CMs) during development.
- Utilized circSamd4 overexpression and silencing in a mouse model of MI.
- Analyzed mitochondrial oxidative stress, DNA damage, CM proliferation, apoptosis, and cardiac function.
- Investigated the molecular mechanism involving Nrf2, Vcp, Vdac1, and the mitochondrial permeability transition pore (mPTP).
Main Results:
- circSamd4 is selectively expressed in fetal and neonatal CMs, regulated by Nrf2.
- circSamd4 overexpression reduced mitochondrial oxidative stress and DNA damage.
- circSamd4 promoted CM proliferation, reduced apoptosis, improved cardiac function, and decreased fibrosis post-MI.
- Mechanistically, circSamd4 induced Vcp translocation, downregulated Vdac1, and prevented mPTP opening.
Conclusions:
- circSamd4 protects the heart from MI by mitigating oxidative stress and maintaining mitochondrial integrity.
- circSamd4 represents a novel therapeutic target for treating heart failure following myocardial infarction.
