Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; Cardiovascular Research Laboratory, Department of Cardiology Pneumology and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Myocardial Infarction Research Laboratory, Department of Cardiology, Pulmonology, and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; Cardiovascular Research Laboratory, Department of Cardiology Pneumology and Angiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Redox Biol. 2022 Aug;54:102370. doi: 10.1016/j.redox.2022.102370. Epub 2022 Jun 18.
Red blood cells (RBCs) were shown to transport and release nitric oxide (NO) bioactivity and carry an endothelial NO synthase (eNOS). However, the pathophysiological significance of RBC eNOS for cardioprotection in vivo is unknown. Here we aimed to analyze the role of RBC eNOS in the regulation of coronary blood flow, cardiac performance, and acute myocardial infarction (AMI) in vivo. To specifically distinguish the role of RBC eNOS from the endothelial cell (EC) eNOS, we generated RBC- and EC-specific knock-out (KO) and knock-in (KI) mice by Cre-induced inactivation or reactivation of eNOS. We found that RBC eNOS KO mice had fully preserved coronary dilatory responses and LV function. Instead, EC eNOS KO mice had a decreased coronary flow response in isolated perfused hearts and an increased LV developed pressure in response to elevated arterial pressure, while stroke volume was preserved. Interestingly, RBC eNOS KO showed a significantly increased infarct size and aggravated LV dysfunction with decreased stroke volume and cardiac output. This is consistent with reduced NO bioavailability and oxygen delivery capacity in RBC eNOS KOs. Crucially, RBC eNOS KI mice had decreased infarct size and preserved LV function after AMI. In contrast, EC eNOS KO and EC eNOS KI had no differences in infarct size or LV dysfunction after AMI, as compared to the controls. These data demonstrate that EC eNOS controls coronary vasodilator function, but does not directly affect infarct size, while RBC eNOS limits infarct size in AMI. Therefore, RBC eNOS signaling may represent a novel target for interventions in ischemia/reperfusion after myocardial infarction.
红细胞（RBCs）被证明可以运输和释放一氧化氮（NO）生物活性物质，并携带内皮型一氧化氮合酶（eNOS）。然而，RBC eNOS 对体内心脏保护的病理生理意义尚不清楚。在这里，我们旨在分析 RBC eNOS 在调节体内冠状动脉血流、心脏功能和急性心肌梗死（AMI）中的作用。为了专门区分 RBC eNOS 与内皮细胞（EC）eNOS 的作用，我们通过 Cre 诱导的 eNOS 失活或再激活，生成了 RBC 和 EC 特异性敲除（KO）和敲入（KI）小鼠。我们发现 RBC eNOS KO 小鼠具有完全保留的冠状动脉扩张反应和 LV 功能。相反，EC eNOS KO 小鼠在分离灌注的心脏中冠状动脉血流反应降低，动脉血压升高时 LV 发展压增加，而每搏量保持不变。有趣的是，RBC eNOS KO 显示出明显增大的梗死面积，并伴有 LV 功能障碍，表现为每搏量和心输出量减少。这与 RBC eNOS KO 中 NO 生物利用度和携氧能力降低一致。至关重要的是，RBC eNOS KI 小鼠在 AMI 后梗死面积减小，LV 功能得到保留。相比之下，与对照组相比，EC eNOS KO 和 EC eNOS KI 在 AMI 后梗死面积或 LV 功能障碍方面没有差异。这些数据表明，EC eNOS 控制冠状动脉血管舒张功能，但不会直接影响梗死面积，而 RBC eNOS 限制 AMI 中的梗死面积。因此，RBC eNOS 信号可能代表心肌梗死后缺血/再灌注干预的一个新靶点。
