Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
Am J Physiol Heart Circ Physiol. 2021 Mar 1;320(3):H1021-H1036. doi: 10.1152/ajpheart.00327.2020. Epub 2021 Jan 22.
Pulmonary hypertension (PH) causes cardiac hypertrophy in the right ventricle (RV) and eventually leads to RV failure due to persistently elevated ventricular afterload. We hypothesized that the mechanical stress on the RV associated with increased afterload impairs vasodilator function of the right coronary artery (RCA) in PH. Coronary vascular response was assessed using microangiography with synchrotron radiation (SR) in two well-established PH rat models, monocrotaline injection or the combined exposure to chronic hypoxia and vascular endothelial growth factor receptor blockade with Su5416 (SuHx model). In the SuHx model, the effect of the treatment with the nonselective endothelin-1 receptor antagonist (ERA), macitentan, was also examined. Myocardial viability was determined in SuHx model rats, using F-FDG Positron emission tomography (PET) and magnetic resonance imaging (MRI). Endothelium-dependent and endothelium-independent vasodilator responses were significantly attenuated in the medium and small arteries of severe PH rats. ERA treatment significantly improved RCA vascular function compared with the untreated group. ERA treatment improved both the decrease in ejection fraction and the increased glucose uptake, and reduced RV remodeling. In addition, the upregulation of inflammatory genes in the RV was almost suppressed by ERA treatment. We found impairment of vasodilator responses in the RCA of severe PH rat models. Endothelin-1 activation in the RCA plays a major role in impaired vascular function in PH rats and is partially restored by ERA treatment. Treatment of PH with ERA may improve RV function in part by indirectly attenuating right heart afterload and in part by associated improvements in right coronary endothelial function. We demonstrated for the first time the impairment of vascular responses in the right coronary artery (RCA) of the dysfunctional right heart in pulmonary hypertensive rats in vivo. Treatment with an endothelin-1 receptor antagonist ameliorated vascular dysfunction in the RCA, enabled tissue remodeling of the right heart, and improved cardiac function. Our results suggest that impaired RCA function might also contribute to the early progression to heart failure in patients with severe pulmonary arterial hypertension (PAH). The endothelium of the coronary vasculature might be considered as a potential target in treatments to prevent heart failure in severe patients with PAH.
肺动脉高压（PH）导致右心室（RV）心肌肥厚，最终由于持续升高的心室后负荷导致 RV 衰竭。我们假设，与后负荷增加相关的 RV 机械应力会损害 PH 中右冠状动脉（RCA）的血管扩张功能。在两种成熟的 PH 大鼠模型中，通过同步辐射（SR）微血管造影评估冠状动脉血管反应：单独注射马兜铃酸或慢性缺氧和血管内皮生长因子受体阻断联合 Su5416（SuHx 模型）。还在 SuHx 模型中检查了非选择性内皮素-1 受体拮抗剂（ERA）马西替坦的治疗效果。在 SuHx 模型大鼠中，使用 F-FDG 正电子发射断层扫描（PET）和磁共振成像（MRI）确定心肌活力。在严重 PH 大鼠的中、小动脉中，内皮依赖性和非内皮依赖性血管扩张反应明显减弱。与未治疗组相比，ERA 治疗显著改善了 RCA 血管功能。ERA 治疗改善了射血分数降低和葡萄糖摄取增加，并减少了 RV 重构。此外，ERA 治疗几乎抑制了 RV 中炎症基因的上调。我们发现严重 PH 大鼠模型的 RCA 血管舒张反应受损。RCA 中的内皮素-1 激活在 PH 大鼠血管功能障碍中起主要作用，并且部分通过 ERA 治疗得到恢复。ERA 治疗 PH 可能通过间接减轻右心后负荷和相关改善右冠状动脉内皮功能来部分改善 RV 功能。我们首次在体内证明了肺动脉高压大鼠功能失调的右心 RCA 血管反应受损。内皮素-1 受体拮抗剂的治疗改善了 RCA 的血管功能障碍，使右心组织重构，并改善了心功能。我们的结果表明，RCA 功能障碍也可能导致严重肺动脉高压（PAH）患者早期进展为心力衰竭。冠状动脉血管的内皮可能被认为是预防严重 PAH 患者心力衰竭的潜在治疗靶点。
