Abstract Body (Do not enter title and authors here): Introduction: Cardiac aging is the main risk factor for cardiovascular disease, and the basis for maintaining cardiovascular system homeostasis and delaying cardiac aging is increasing mitophagy to promote the clearance of damaged mitochondria. Suv39h1 is a histone lysine methyltransferase closely associated with aging, but it is not yet clear whether Suv39h1 is associated with cardiac aging.
Hypothesis: Whether downregulating Suv39h1 signaling improves cardiac aging, and if so to further explore underlying mechanism.
Methods: H9C2 cardiomyocytes were stimulated with 0.1μmol doxorubicin for 24h to induce aging. Recombinant Suv39h1 lentivirus was infected with H9C2 cells to overexpress or knock down Suv39h1. The aging-associated phenotypes of cardiomyocytes was detected by western blot and β-galactosidase staining. Mitochondrial membrane potential was detected by JC-1 staining. The effect of Suv39h1 on aging phenotype was detected by β-galactosidase staining. Mitochondrial autophagy markers were detected by western blot.
Results: Compared with the control group, the expression of aging marker P21 and positive staining of SA-β-gal were significantly increased in Doxorubicin induced subacute senescent cardiomyocytes. The expressions of Suv39h1 and H3K9me3 were also significantly increased in aging cardiomyocytes.Compared with sh-Con group, mitochondrial membrane potential of cardiomyocytes increased significantly in sh-Suv39h1group,indicating that down-regulated Suv39h1 reversed doxorubicin- induced mitochondrial membrane potential decline of cardiomyocytes. β-galactosidase staining showed that the positive rate of SA-β-gal in sh-Suv39h1 group was significantly lower than that in sh-Con group, indicating that cell senescence was inhibited. However, overexpression of Suv39h1 showed the opposite result.Mechanistically,down-regulation of Suv39h1 can relieve transcriptional inhibition of H3K9me3 on SIRT1, and promote mitochondrial autophagy through activation of Pink1/Parkin axis, delaying cardiac aging.
Conclusions: Targeted down-regulation of Suv39h1 can relieve the transcriptional inhibition of H3K9me3 on SIRT1, promote myocardial mitochondrial autophagy and alleviate cardiac aging.