Overexpression of mitochondrial transcription factor a prevents mitochondrial deficiencies and cardiac failure after myocardial infarction

Abstract

Purpose: Mitochondrial transcription factor A (Tfam) is a nuclear-encoded gene product that is incorporated into the mitochondria and is required for the transcription/replication of mitochondrial DNA (mtDNA). Both Tfam expression and mtDNA copy number have been shown to be decreased in the failing heart. We hypothesized that the overexpression of Tfam could inhibit mitochondrial deficiencies as well as left ventricular (LV) remodeling and failure in mice after myocardial infarction (MI). Methods: We created MI in human Tfam transgenic mice (TG + MI) and nontransgenic wild-type littermates (WT + MI) by coronary artery ligation. Results: Human Tfam protein was expressed in the hearts from TG mice, whereas the endogenous expression of mouse Tfam was not affected. MtDNA copy number as well as complex III and IV activities were decreased in WT + MI, both of which preserved normal in TG + MI. Survival rate during 4 weeks of MI was significantly greater in TG + MI than in WT + MI (100 vs. 66%, P < 0.01) despite the comparable infarct size and aortic pressure between groups. LV cavity dilatation and contractile dysfunction by echocardiography were significantly attenuated in TG + MI, which was accompanied by a decrease in myocyte hypertrophy and interstitial fibrosis in the noninfarcted LV. Conclusion: Overexpression of Tfam improved survival and inhibited LV remodeling and failure after MI. Therapies designed to interfere with mtDNA deficiencies might be beneficial to prevent cardiac failure.