Overexpression of mitochondrial transcription factor A ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction
Overexpression of mitochondrial transcription factor A ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction
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DOI：
10.1161/circulationaha.104.524835
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发表时间：
2005-08-02
期刊：
影响因子：
37.8
通讯作者：
Tsutsui, H
中科院分区：
文献类型：
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作者：
Ikeuchi, M;Matsusaka, H;Tsutsui, H
背景 - 线粒体 DNA (mtDNA) 拷贝数不仅在 mtDNA 突变疾病中减少，而且在多种获得性退行性和缺血性疾病中也减少。线粒体转录因子 A (TFAM) 对于 mtDNA 转录和复制至关重要。心力衰竭时心肌 mtDNA 拷贝数和 TFAM 表达均下降。然而，TFAM 在这种疾病状态下的功能意义尚未确定。方法和结果 - 我们现在通过创建过度表达人类 TFAM 基因的转基因 (Tg) 小鼠来解决这个问题，并检查 TFAM 是否可以保护心脏免受 mtDNA 缺陷的影响，并在结扎左冠状动脉造成心肌梗塞 (MI) 后减轻左心室 (LV) 重塑和衰竭。 TFAM 过表达可以改善 MI 后心脏中 mtDNA 拷贝数和线粒体复合酶活性的下降。尽管梗死面积相当，但 Tg-MI 中 MI 4 周的存活率显着高于野生型 (WT) 同窝小鼠 (WT-MI)。 Tg-MI 中左室腔扩张和功能障碍显着减弱。 WT-MI 中左心室舒张末压升高，Tg-MI 中左室舒张末压降低。 Tg-MI 中左心室功能的改善伴随着心肌细胞肥大、细胞凋亡、间质纤维化以及非梗死左心室氧化应激的减少。结论 - TFAM 过度表达抑制 MI 后左心室重塑。 TFAM可能为心力衰竭提供一种新的治疗策略。
Background - Mitochondrial DNA (mtDNA) copy number is decreased not only in mtDNA-mutation diseases but also in a wide variety of acquired degenerative and ischemic diseases. Mitochondrial transcription factor A (TFAM) is essential for mtDNA transcription and replication. Myocardial mtDNA copy number and TFAM expression both decreased in cardiac failure. However, the functional significance of TFAM has not been established in this disease state.Methods and Results - We have now addressed this question by creating transgenic (Tg) mice that overexpress human TFAM gene and examined whether TFAM could protect the heart from mtDNA deficiencies and attenuate left ventricular (LV) remodeling and failure after myocardial infarction (MI) created by ligating the left coronary artery. TFAM overexpression could ameliorate the decrease in mtDNA copy number and mitochondrial complex enzyme activities in post-MI hearts. Survival rate during 4 weeks of MI was significantly higher in Tg-MI than in wild-type (WT) littermates (WT-MI), although infarct size was comparable. LV cavity dilatation and dysfunction were significantly attenuated in Tg-MI. LV end-diastolic pressure was increased in WT- MI, and it was also reduced in Tg-MI. Improvement of LV function in Tg-MI was accompanied by a decrease in myocyte hypertrophy, apoptosis, and interstitial fibrosis as well as oxidative stress in the noninfarcted LV.Conclusions - Overexpression of TFAM inhibited LV remodeling after MI. TFAM may provide a novel therapeutic strategy of cardiac failure.