雷帕霉素靶蛋白抑制剂对心肌梗死后左心室重构的有益作用。

Beneficial effects of Mammalian target of rapamycin inhibition on left ventricular remodeling after myocardial infarction.

机构信息

Department of Cardiology, University of Heidelberg, Heidelberg, Germany.

出版信息

J Am Coll Cardiol. 2009 Dec 15;54(25):2435-46. doi: 10.1016/j.jacc.2009.08.031.

DOI:10.1016/j.jacc.2009.08.031

PMID:20082935

Abstract

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 + or - 0.3 mm vs. 11.4 + or - 0.2 mm, p < 0.05), end-diastolic volumes (304 + or - 30 microl vs. 414 + or - 16 microl, 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.

摘要

目的

心肌梗死（MI）后，不良心肌重构的程度对预后有重要影响。本研究旨在探讨抑制“雷帕霉素靶蛋白”（mTOR）是否能减轻 MI 后的左心室重构。

背景

目前，抑制重构的治疗策略仅限于抑制神经体液激活。mTOR 依赖性信号机制在重构过程中起着核心作用，为治疗提供了新的机会。

方法

在大鼠 MI 后第 1 天或第 3 天开始给予依维莫司（RAD）治疗。

结果

28 天后，RAD 治疗组动物的 MI 后重构减轻，LV 功能改善，LV 舒张末期直径减小（8.9 ± 0.3 mm 比 11.4 ± 0.2 mm，p < 0.05），舒张末期容积减小（304 ± 30 μl 比 414 ± 16 μl，p < 0.05），心肌细胞大小减小（与载体相比减少 40%，p < 0.05）。与载体治疗组相比，梗死面积明显减小。mTOR 抑制增加了 MI 边缘区的自噬，同时降低了蛋白酶体活性。自噬流的测量表明，RAD 并没有减少自噬体的清除。当 RAD 治疗在 MI 后 3 天开始时，不良重构仍然减轻，自噬仍然增加。即使在 1 个月后停止 RAD 治疗，MI 后 3 个月仍观察到 LV 功能持续改善。