The 'no reflow' phenomenon, where the coronary artery is patent after treatment of acute myocardial infarction (AMI) but tissue perfusion is not restored, is associated with worse outcome. The mechanism of no reflow is unknown. We hypothesized that pericytes contraction, in an attempt to maintain a constant capillary hydrostatic pressure during reduced coronary perfusion pressure, causes capillary constriction leading to no reflow, and that this effect is mediated through the orphan receptor, GPR39, present in pericytes. We created AMI (coronary occlusion followed by reperfusion) in GPR39 knock out mice and littermate controls. In a separate set of experiments we treated wild-type mice undergoing coronary occlusion with vehicle or VC43, a specific inhibitor of GPR39, prior to reperfusion. We found that no reflow zones were significantly smaller in the GPR39 knockouts compared to controls. Both no reflow and infarct size were also markedly smaller in animals treated with VC43 compared with vehicle. Immunohistochemistry revealed greater capillary density and larger capillary diameter at pericyte locations in the GPR39 knockout and VC43 treated mice compared to controls. We conclude that GPR39 mediated pericyte contraction during reduced coronary perfusion pressure causes capillary constriction resulting in no reflow during AMI, and that smaller no reflow zones in GPR39 knockout and VC43 treated animals are associated with smaller infarct sizes. These results elucidate the mechanism of no reflow in AMI as well as providing a therapeutic pathway for the condition.

中文翻译：

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急性心肌梗死后“无复流”现象的机制和潜在治疗：周细胞和 GPR39 的作用


“无复流”现象是指急性心肌梗死 (AMI) 治疗后冠状动脉畅通但组织灌注未恢复，这种现象与较差的结果相关。不回流的机制尚不清楚。我们假设，在冠状动脉灌注压降低期间，周细胞收缩试图维持恒定的毛细血管静水压，导致毛细血管收缩，导致无回流，并且这种效应是通过周细胞中存在的孤儿受体 GPR39 介导的。我们在 GPR39 敲除小鼠和同窝对照小鼠中创建了 AMI（冠状动脉闭塞，然后再灌注）。在另一组实验中，我们在再灌注前用载体或 VC43（GPR39 的特异性抑制剂）治疗经历冠状动脉闭塞的野生型小鼠。我们发现，与对照相比，GPR39 敲除型中的回流区没有明显更小。与媒介物相比，用 VC43 治疗的动物的无复流和梗塞面积也明显较小。免疫组织化学显示，与对照组相比，GPR39 敲除和 VC43 处理的小鼠周细胞位置的毛细血管密度更大，毛细血管直径更大。我们得出的结论是，在冠状动脉灌注压降低期间，GPR39介导的周细胞收缩导致毛细血管收缩，导致AMI期间无复流，并且GPR39敲除和VC43治疗的动物中较小的无复流区与较小的梗塞面积相关。这些结果阐明了 AMI 中无复流的机制，并为该疾病提供了治疗途径。