DNA hypomethylation by fisetin preserves mitochondria functional genes and contributes to the protection of I/R rat heart.

Abstract

Myocardial I/R can alter the expression of different sets of cardiac genes that negatively influence the I/R outcome via epigenetic modifications. Fisetin is known to be cardioprotective against I/R, but its underlying epigenetic mode of action is not known and is addressed in the present study. Male Wistar rats were subjected to I/R by using the Langendorff perfusion system. Fisetin (20mg/kg; i.p.) was administered before I/R induction, followed by the measurement of cardiac injury, hemodynamics, physiological indices, the differential expression of genes that regulate DNA methylation, and the function of mitochondria were performed. Fisetin administered I/R rat heart significantly reduced the global DNA hypermethylation and infarct size with an improved physiological recovery, measured via RPP (81%) and LVDP (82%) from the I/R control. Additionally, we noted decreased expression of the DNMT1 gene by 35% and increased expression of the TET1, TET2, and TET3 genes in fisetin-treated I/R rat hearts. Molecular docking analysis data reveals that the fisetin inhibits DNMT1 at the substrate binding site with minimum binding energy (- 8.2kcal/mol) compared to the DNMT1 inhibitor, 5-azacytidine. Moreover, fisetin-treated I/R heart reversed the expression of the I/R-linked declined expression of bioenergetics genes (MT-ND1, MT-ND2, MT-ND4, MT-Cyt B, MT-COX1, MT-COX2, MT-ATP6), mitochondrial fission gene (Fis1), replication control genes PGC-1α, POLG, and TFAM to near-normal level. Based on the above findings, we demonstrated that fisetin possesses the ability to modulate the expression of different mitochondrial genes via influencing the global DNA methylation in cardiac tissue, which contributes significantly to the improved contractile function and thereby renders cardioprotection against I/R.