Nrf3-Mediated Mitochondrial Superoxide Promotes Cardiomyocyte Apoptosis and Impairs Cardiac Functions by Suppressing Pitx2
Authors' conclusion
Nrf3 promotes injury-induced CM apoptosis and deteriorates cardiac functions by increasing mitochondrial ROS production through suppressing Pitx2 expression.
Study context
- Population
- Mice subjected to myocardial infarction (MI) or ischemia/reperfusion injury; primary neonatal mouse and rat ventricular myocytes and human iPSC-derived cardiomyocyte (CMs)
- Comparison
- Nrf3 knockout vs wild-type in MI or ischemia/reperfusion injury
Methodological detailsglobal and CM-specific Nrf3 knockout mice, human iPSC-derived CMs, ChIP-seq, AAV vectors
- Global and CM-specific Nrf3 knockout mice
- Human iPSC-derived CMs
- ChIP-seq
- AAV vectors
Main finding
As reported in the abstract
- Nrf3 increased in CMs within border zone of infarcted human hearts and murine cardiac tissue after MI
- Global and CM-specific Nrf3 knockout decreased injury-induced mitochondrial reactive oxygen species (ROS), CM apoptosis and pathological cardiac remodeling, improving cardiac function
- Cardiac-specific Nrf3 overexpression reversed the ameliorative phenotypes in Nrf3-KO mice
- Augmenting mitochondrial ROS with MitoParaquat blunted the benefits of Nrf3 deletion
- Nrf3 binds Pitx2 promoter, increasing DNA methylation via hnRNP K and DNMT1, inhibiting Pitx2 expression
- CM-specific Pitx2 knockdown blunted the benefits of Nrf3 deletion; cardiac-specific Pitx2 overexpression attenuated MI-induced mitochondrial ROS and CM apoptosis and preserved cardiac function
Original publication
Nrf3-Mediated Mitochondrial Superoxide Promotes Cardiomyocyte Apoptosis and Impairs Cardiac Functions by Suppressing Pitx2. Circulation. Published 18 March 2025. doi:10.
Summarised from the published abstract; every number is checked against it