Evaluation of right coronary vascular dysfunction in severe pulmonary hypertensive rats using synchrotron radiation microangiography
Evaluation of right coronary vascular dysfunction in severe pulmonary hypertensive rats using synchrotron radiation microangiography
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DOI：
10.1152/ajpheart.00327.2020
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发表时间：
2021-03-01
影响因子：
4.8
通讯作者：
Nakaoka, Yoshikazu
中科院分区：
文献类型：
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作者：
Inagaki, Tadakatsu;Pearson, James T.;Nakaoka, Yoshikazu
肺动脉高压（PH）导致右心室（RV）心肌肥厚，并最终导致RV衰竭，原因是持续升高的心室后负荷。我们假设，RV上的机械应力与增加后负荷损害右冠状动脉（RCA）在PH的血管扩张功能。冠状动脉血管反应进行了评估，使用微血管造影与同步辐射（SR）在两个良好的PH大鼠模型，野百合碱注射或联合暴露于慢性缺氧和血管内皮生长因子受体阻断与Su 5416（SuHx模型）。在SuHx模型中，还检查了非选择性内皮素-1受体拮抗剂（ERA）马昔腾坦给药的影响。使用F-18-FDG正电子发射断层扫描（PET）和磁共振成像（MRI）在SuHx模型大鼠中测定心肌活力。重度PH大鼠中、小动脉内皮依赖性和非内皮依赖性血管舒张反应明显减弱。与未治疗组相比，ERA治疗显著改善RCA血管功能。ERA治疗改善了射血分数的降低和葡萄糖摄取的增加，并减少了RV重塑。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中血管舒张反应受损。RCA中的内皮素-1活化在PH大鼠的血管功能受损中起主要作用，并通过ERA治疗部分恢复。用ERA治疗PH可以通过间接衰减右心后负荷和部分地通过相关的改善右冠状动脉内皮功能来改善RV功能。新&值得注意的是，我们第一次证明了在肺动脉高压大鼠体内功能障碍的右心的右冠状动脉（RCA）中血管反应的损害。用内皮素-1受体拮抗剂治疗可改善RCA的血管功能障碍，使右心组织重塑，并改善心功能。我们的研究结果表明，RCA功能受损也可能导致严重肺动脉高压（PAH）患者早期进展为心力衰竭。冠状动脉血管内皮可能被认为是预防重度PAH患者心力衰竭治疗的潜在靶点。
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-18-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.NEW & NOTEWORTHY 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.