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.