IGF, CNRS, INSERM, Univ. Montpellier, F-34094 Montpellier, France.
Laboratory of Excellence Ion Channel Science and Therapeutics, F-06560 Valbonne.
Cardiovasc Res. 2017 May 1;113(6):644-655. doi: 10.1093/cvr/cvx024.
In a previous study using a genome-wide microarray strategy, we identified metabotropic glutamate receptor 1 (mGluR1) as a putative cardioprotective candidate in ischaemic postconditioning (PostC). In the present study, we investigated the role of cardiac mGluR1 receptors during cardioprotection against myocardial ischaemia-reperfusion injury in the mouse myocardium.
mGluR1 activation by glutamate administered 5 min before reperfusion in C57Bl/6 mice subjected to a myocardial ischaemia protocol strongly decreased both infarct size and DNA fragmentation measured at 24 h reperfusion. This cardioprotective effect was mimicked by the mGluR1 agonist, DHPG (10 μM), and abolished when glutamate was coinjected with the mGluR1 antagonist YM298198 (100 nM). Wortmannin (100 nM), an inhibitor of PI3-kinase, was able to prevent glutamate-induced cardioprotection. A glutamate bolus at the onset of reperfusion failed to protect the heart of mGluR1 knockout mice subjected to a myocardial ischaemia-reperfusion protocol, although PostC still protected the mGluR1 KO mice. Glutamate-treatment improved post-infarction functional recovery as evidenced by an echocardiographic study performed 15 days after treatment and by a histological evaluation of fibrosis 21 days post-treatment. Interestingly, restoration of functional mGluR1s by a PostC stimulus was evidenced at the transcriptional level. Since mGluR1s were localized at the surface membrane of cardiomyocytes, they might contribute to the cardioprotective effect of ischaemic PostC as other Gq-coupled receptors.
This study provides the first demonstration that mGluR1 activation at the onset of reperfusion induces cardioprotection and might represent a putative strategy to prevent ischaemia-reperfusion injury.
在之前的一项使用全基因组微阵列策略的研究中，我们发现代谢型谷氨酸受体 1（mGluR1）是缺血后处理（PostC）中的一个潜在的心脏保护候选物。在本研究中，我们研究了心脏 mGluR1 受体在小鼠心肌缺血再灌注损伤中的心脏保护作用。
在 C57Bl/6 小鼠的心肌缺血方案中，在再灌注前 5 分钟给予谷氨酸激活 mGluR1，强烈降低了 24 小时再灌注时的梗死面积和 DNA 片段化。这种心脏保护作用被 mGluR1 激动剂 DHPG（10 μM）模拟，并且当谷氨酸与 mGluR1 拮抗剂 YM298198（100 nM）共注射时被消除。PI3-激酶抑制剂 wortmannin（100 nM）能够阻止谷氨酸诱导的心脏保护作用。在再灌注开始时给予谷氨酸灌流未能保护接受心肌缺血再灌注方案的 mGluR1 敲除小鼠的心脏，尽管 PostC 仍然保护 mGluR1 KO 小鼠。谷氨酸处理改善了梗死后的功能恢复，这可以通过治疗后 15 天进行的超声心动图研究和治疗后 21 天的纤维化组织学评估来证明。有趣的是，通过 PostC 刺激恢复功能性 mGluR1s 在转录水平上得到了证明。由于 mGluR1s 定位于心肌细胞膜表面，它们可能作为其他 Gq 偶联受体对缺血后处理的心脏保护作用做出贡献。
本研究首次证明，在再灌注开始时激活 mGluR1 可诱导心脏保护作用，可能是预防缺血再灌注损伤的一种潜在策略。
