Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China.
Department of Pathophysiology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
J Cell Mol Med. 2020 Dec;24(24):14514-14524. doi: 10.1111/jcmm.16078. Epub 2020 Nov 9.
Hypoxic coronary vasospasm may lead to myocardial ischaemia and cardiac dysfunction. Inosine 3',5'-cyclic monophosphate (cIMP) is a putative second messenger to mediate this pathological process. Nevertheless, it remains unclear as to whether levels of cIMP can be regulated in living tissue such as coronary artery and if so, what is the consequence of this regulation on hypoxia-induced vasoconstriction. In the present study, we found that cIMP was a key determinant of hypoxia-induced constriction but not that of the subsequent relaxation response in porcine coronary arteries. Subsequently, coronary arteries were treated with various phosphodiesterase (PDE) inhibitors to identify PDE types that are capable of regulating cIMP levels. We found that inhibition of PDE1 and PDE5 substantially elevated cIMP content in endothelium-denuded coronary artery supplemented with exogenous purified cIMP. However, cGMP levels were far lower than their levels in intact coronary arteries and lower than cIMP levels measured in endothelium-denuded coronary arteries supplemented with exogenous cIMP. The increased cIMP levels induced by PDE1 or PDE5 inhibition further led to augmented hypoxic constriction without apparently affecting the relaxation response. In intact coronary artery, PDE1 or PDE5 inhibition up-regulated cIMP levels under hypoxic condition. Concomitantly, cGMP level increased to a comparable level. Nevertheless, the hypoxia-mediated constriction was enhanced in this situation that was largely compromised by an even stronger inhibition of PDEs. Taken together, these data suggest that cIMP levels in coronary arteries are regulated by PDE1 and PDE5, whose inhibition at a certain level leads to increased cIMP content and enhanced hypoxic constriction.
缺氧性冠状动脉痉挛可导致心肌缺血和心功能障碍。肌苷酸 3',5'-环单磷酸（cIMP）是介导这一病理过程的假定第二信使。然而，cIMP 的水平是否可以在冠状动脉等活体组织中进行调节，以及如果可以调节，这种调节对缺氧诱导的血管收缩有什么影响，目前仍不清楚。在本研究中，我们发现 cIMP 是缺氧诱导收缩的关键决定因素，但不是猪冠状动脉随后的舒张反应的关键决定因素。随后，用各种磷酸二酯酶（PDE）抑制剂处理冠状动脉，以确定能够调节 cIMP 水平的 PDE 类型。我们发现，抑制 PDE1 和 PDE5 可显著提高内皮细胞去除的冠状动脉中 cIMP 的含量，同时补充外源性纯化的 cIMP。然而，cGMP 水平远低于完整冠状动脉中的水平，也低于内皮细胞去除的冠状动脉中补充外源性 cIMP 时测量的 cIMP 水平。PDE1 或 PDE5 抑制引起的 cIMP 水平升高进一步导致缺氧性收缩增强，而对舒张反应没有明显影响。在完整的冠状动脉中，PDE1 或 PDE5 抑制可在缺氧条件下增加 cIMP 水平。同时，cGMP 水平增加到相当水平。然而，在这种情况下，缺氧介导的收缩增强，这在很大程度上被 PDE 更强的抑制所抵消。综上所述，这些数据表明，冠状动脉中 cIMP 的水平受 PDE1 和 PDE5 的调节，其在一定水平的抑制会导致 cIMP 含量增加和缺氧性收缩增强。
