Abstract
BackgroundMitochondrial transcription factor A (TFAM) is essential for the maintenance of mitochondrial DNA (mtDNA). TFAM overexpression increases mtDNA copy number, prevents cardiac remodeling and improves survival after myocardial infarction. However, the role of the increased mtDNA copy number in volume overload (VO) remains unknown.Methods and ResultsWe used TFAM and Twinkle (TW) transgenic (TG) mice, both of which nearly doubled the mtDNA copy number in heart. One day after creating the aortocaval shunt to induce VO, left ventricular (LV) end diastolic pressures equally increased in all groups, and TFAM and TW significantly suppressed increased mRNAs of matrix metalloprotease (MMP) ‐9 and connective tissue growth factor. In 8 weeks after operation, both TFAM and TW prevented LV dysfunction (LV ejection fraction: TFAM 53.6±2.5, TW 54.0±1.0, WT 37.1±1.9, 39.1±3.0, p<0.01), dilatation (LV diastolic dimension: TFAM 4.6±0.1, TW 4.3±0.1, WT 5.0±0.1, 4.9±0.1, p<0.01) and perivascular fibrosis. They also suppressed superoxide (TFAM −21%, TW −31% vs. each wild type VO group, p<0.05) and MMP activity (TFAM −31%, TW −23% vs. each wild type VO group, p<0.05).ConclusionOverexpressed TFAM or TW equally ameliorated VO‐induced eccentric cardiac remodeling, which suggests that increased mtDNA copy number plays a key role in anti‐remodeling effects of TFAM and TW via suppression of MMP activity and fibrosis.
Published Version
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