SIRT1 deficiency promotes age-related heart failure through enhancing ferroptosis via GATA4-HADHA-GPX4 axis - PubMed
4 hours ago
- #aging
- #heart failure
- #ferroptosis
- Aging is a major contributor to the increasing prevalence of heart failure (HF).
- Ferroptosis, a form of cell death, is implicated in age-related disorders and cardiovascular diseases.
- Aged rats show impaired cardiac function with signs of ferroptosis, including reduced GPX4 expression and excessive lipid peroxidation.
- Cardiomyocyte-specific GPX4 knockout mice develop worsened cardiac ferroptosis and dysfunction.
- Iron overload worsens ferroptotic injury and cardiac dysfunction in aged rats, while ferroptosis inhibitors alleviate these effects.
- Overexpression of GPX4 in aging mice via rAAV9 reduces ferroptosis and preserves cardiac function.
- Proteomic analysis identifies HADHA as downregulated in aging hearts, especially under iron overload.
- HADHA deficiency leads to mitochondrial dysfunction, ROS overproduction, glutathione depletion, GPX4 suppression, and ferroptosis.
- SIRT1 is identified as an upstream regulator of HADHA during cardiac aging, with reduced SIRT1 expression suppressing HADHA via GATA4 inhibition.
- SIRT1 overexpression or activation (e.g., by resveratrol) restores HADHA, suppresses ferroptosis, and protects against HF in aging models.