Beneficial Effects of Mammalian Target of Rapamycin Inhibition on Left Ventricular Remodeling After Myocardial Infarction
Beneficial Effects of Mammalian Target of Rapamycin Inhibition on Left Ventricular Remodeling After Myocardial Infarction
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DOI：
10.1016/j.jacc.2009.08.031
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发表时间：
2009-12-15
影响因子：
24
通讯作者：
Hardt, Stefan E.
中科院分区：
文献类型：
--
作者：
Buss, Sebastian J.;Muenz, Sebastian;Hardt, Stefan E.
目的不良心肌重构的程度对心肌梗死（MI）后的预后有重要影响。在这项研究中，我们研究了抑制“哺乳动物雷帕霉素靶点”（mTOR）是否会减轻心肌梗死后左心室（LV）重构。背景抑制重构的治疗策略目前仅限于抑制神经体液激活。mtor依赖的信号机制主要参与重塑过程，并提供新的治疗机会。方法依维莫司（Everolimus， RAD）在大鼠心肌梗死（MI）诱导后第1天或第3天给予治疗。结果28天后，接受rad治疗的动物心肌梗死后重构减轻，左室功能改善，左室舒张末期直径减小（8.9 +/- 0.3 mm vs. 11.4 +/- 0.2 mm, p < 0.05），舒张末期体积减小（304 +/- 30 μ l vs. 414 +/- 16 μ l, p < 0.05），心肌细胞大小减小（与对照组相比-40%，p < 0.05）。与给药动物相比，梗死面积明显减小。mTOR抑制增加了自噬，同时降低了梗死心肌边界区蛋白酶体的活性。自噬通量测量表明，RAD不降低自噬体清除。当心肌梗死后3天开始RAD治疗时，不良重构仍然减弱，自噬仍然增加。心肌梗死后3个月观察到左室功能持续改善，即使在1个月后停用RAD治疗。结论mTOR抑制是限制心肌梗死面积和减轻心肌梗死后不良左室重构的潜在治疗策略[J] . journal of Cardiology, 2009; 54: 2435-46) (C) 2009
Objectives The extent of adverse myocardial remodeling contributes essentially to the prognosis after myocardial infarction (MI). In this study we investigated whether inhibition of "mammalian target of rapamycin" (mTOR) attenuates left ventricular (LV) remodeling after MI.Background Therapeutic strategies to inhibit remodeling are currently limited to inhibition of neurohumoral activation. The mTOR-dependent signaling mechanisms are centrally involved in remodeling processes and provide new therapeutic opportunities.Methods Everolimus (RAD) treatment was initiated on the day after or 3 days after induction of myocardial infarction (MI) in rats.Results After 28 days, RAD-treated animals had reduced post-MI remodeling, with improved LV function and smaller LV end-diastolic diameters (8.9 +/- 0.3 mm vs. 11.4 +/- 0.2 mm, p < 0.05), end-diastolic volumes (304 +/- 30 mu l vs. 414 +/- 16 mu l, p < 0.05), and cardiac myocyte size (-40% vs. vehicle, p < 0.05). Infarct size was significantly reduced compared with vehicle-treated animals. The mTOR inhibition increased autophagy and concomitantly decreased proteasome activity in the border zone of the infarcted myocardium. Measurement of autophagic flux demonstrated that RAD did not decrease autophagosome clearance. When RAD treatment was initiated 3 days after MI, adverse remodeling was still attenuated and increased autophagy was still present. Sustained improvement of LV function was observed 3 months after MI, even when RAD treatment was discontinued after 1 month.Conclusions Inhibition of mTOR is a potential therapeutic strategy to limit infarct size and to attenuate adverse LV remodeling after MI. (J Am Coll Cardiol 2009; 54: 2435-46) (C) 2009 by the American College of Cardiology Foundation