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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Epigenetic blockade of SOD2 boosts mitochondria ROS and cytoskeleton remodelling in cardiac fibrosis
Yun-Sen Zhang1, Zhen-Yu Liu1, Li-Chan Lin1
1Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, P.R. China.
Aims:
Mitochondria reactive oxygen species (ROS) play a critical role in the progression of cardiac fibrosis. Nonetheless, the role of mitochondria ROS in cardiac fibroblasts cytoskeletal remodelling and ferroptosis have not been explored. However, little is known about the epigenetic mechanisms through mitochondria ROS, cytoskeletal remodelling and ferroptosis in cardiac fibrosis (CF).
Methods And Results:
Cardiac fibroblast-specific methyl-CpG-binding protein 2 (MeCP2)-deficient mice and wild type mice were treated with Isoprenaline to induce replacement cardiac fibrosis. AAV9 carrying fibroblast-specific POSTN promoter-driven small hairpin RNA targeting superoxide dismutase 2(SOD2), and overexpression of SOD2 were administered to investigate their vital roles in cardiac fibrosis. Biochemical and histological analyses were performed to determine how MeCP2 transcriptional repression of SOD2 through mitochondria ROS, cytoskeletal remodelling and ferroptosis in cardiac fibrosis. The reconstitution of SOD2 in MeCP2-deficient cardiac fibroblasts and mouse hearts was performed to study its effect on mitochondria ROS, cytoskeletal remodelling, ferroptosis and fibrosis. Human heart tissue from patients with atrial fibrillation is used for translational validation. Downregulation of SOD2 in replacement cardiac fibrosis is associated with increased mitochondria ROS, decreased mitochondrial membrane potential (MMP), and enhanced cytoskeletal remodelling. Fibroblasts-specific SOD2 deficiency enhances mitochondrial ROS, decreases MMP, promotes cytoskeletal remodelling and fibroblasts ferroptosis, leading to cardiac fibrosis. Specifically, SOD2 downregulation is associated with elevated CpG 5mC levels. Mechanistically, methyl-CpG binding protein MeCP2 recognizes bond to SOD2 CpG 5mC and recruits H3K27me3, resulting in SOD2 transcriptional repression. MeCP2 knockdown rescues SOD2 inhibition and mitigates cytoskeletal remodelling, ferroptosis and fibrosis. In addition, human atrial fibrillation fibrotic atrial tissue exhibits signs of MeCP2 upregulation, SOD2 inhibition, elevated mitochondria ROS, and ferroptosis.
Conclusion:
We demonstrated a novel epigenetic mechanism through which silencing of SOD2 boosts mitochondria ROS, cytoskeletal remodelling, ferroptosis and promotes cardiac fibrosis. Our findings provide new insights for the development of preventive measures for replacement cardiac fibrosis.
Insights
Silencing of superoxide dismutase 2 (SOD2) boosts mitochondrial reactive oxygen species (ROS), cytoskeletal remodeling, and ferroptosis, promoting cardiac fibrosis. Targeting the MeCP2/SOD2 epigenetic axis offers a potential therapeutic strategy for cardiac fibrosis.
Area of Science:
- Cardiovascular Biology
- Epigenetics
- Cellular Biology
Background:
- Mitochondrial reactive oxygen species (ROS) are implicated in cardiac fibrosis progression.
- The roles of mitochondrial ROS in cardiac fibroblast cytoskeletal remodeling and ferroptosis remain underexplored.
- Epigenetic mechanisms linking mitochondrial ROS, cytoskeletal remodeling, and ferroptosis in cardiac fibrosis are largely unknown.
Purpose of the Study:
- To investigate the epigenetic regulation of mitochondrial ROS, cytoskeletal remodeling, and ferroptosis in cardiac fibrosis.
- To elucidate the role of methyl-CpG-binding protein 2 (MeCP2) and superoxide dismutase 2 (SOD2) in cardiac fibrosis.
- To explore the therapeutic potential of targeting the MeCP2/SOD2 axis.
Main Methods:
- Utilized cardiac fibroblast-specific MeCP2-deficient and wild-type mice treated with Isoprenaline to induce cardiac fibrosis.
- Employed AAV9 vectors for fibroblast-specific SOD2 knockdown or overexpression.
- Conducted biochemical and histological analyses, including SOD2 reconstitution studies and analysis of human atrial fibrillation tissue.
Main Results:
- Downregulation of SOD2 in cardiac fibrosis correlated with increased mitochondrial ROS, reduced mitochondrial membrane potential, and enhanced cytoskeletal remodeling.
- Fibroblast-specific SOD2 deficiency exacerbated mitochondrial ROS, promoted cytoskeletal remodeling and ferroptosis, leading to cardiac fibrosis.
- MeCP2 epigenetically represses SOD2 via CpG 5mC binding and H3K27me3 recruitment, and MeCP2 knockdown mitigated fibrosis.
Conclusions:
- Demonstrated a novel epigenetic mechanism where SOD2 silencing promotes cardiac fibrosis through increased mitochondrial ROS, cytoskeletal remodeling, and ferroptosis.
- The MeCP2/SOD2 axis plays a critical role in mitigating replacement cardiac fibrosis.
- Targeting SOD2 DNA methylation, cytoskeletal remodeling, and ferroptosis presents a promising therapeutic strategy for cardiac fibrosis.
