Biomedicines (Nov 2022)
Diabetic Hearts Exhibit Global DNA Hypermethylation That Alter the Mitochondrial Functional Genes to Enhance the Sensitivity of the Heart to Ischemia Reperfusion Injury
Abstract
A recent study has shown that DNA hypermethylation can promote ischemia reperfusion (I/R) injury by regulating the mitochondrial function. Diabetes mellitus (DM) is reported to induce DNA hypermethylation, but whether this prior DNA methylation in DM I/R heart inflicts a beneficial or detrimental effect is not known and is addressed in this study. DM was induced in 6-week-old male Wistar rats with streptozotocin (65 mg/kg b.wt). After 24 weeks on a normal diet, I/R was induced in rat heart using a Langendorff perfusion system and analyzed the myocardium for different parameters to measure hemodynamics, infarct size, DNA methylation and mitochondrial function. Diabetic heart exhibited DNA hypermethylation of 39% compared to the control, along with DNMT expression elevated by 41%. I/R induction in diabetic heart promoted further DNA hypermethylation (24%) with aggravated infarct size (21%) and reduced the cardiac rate pressure product (43%) from I/R heart. Importantly, diabetic I/R hearts also experienced a decline in the mitochondrial copy number (60%); downregulation in the expression of mitochondrial bioenergetics (ND1, ND2, ND3, ND4, ND5, ND6) and mitofusion (MFN1, MFN2) genes and the upregulation of mitophagy (PINK, PARKIN, OPTN) and mitofission (MFF, DNM1, FIS1) genes that reduce the dp/dt contribute to the contractile dysfunction in DM I/R hearts. Besides, a negative correlation was obtained between mitochondrial PGC1α, POLGA, TFAM genes and DNA hypermethylation in DM I/R hearts. Based on the above data, the elevated global DNA methylation level in diabetic I/R rat hearts deteriorated the mitochondrial function by downregulating the expression of POLGA, TFAM and PGC1α genes and negatively contributed to I/R-associated increased infarct size and altered hemodynamics.
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