Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
Unit of Cardiology, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
Purinergic Signal. 2017 Sep;13(3):319-329. doi: 10.1007/s11302-017-9563-6. Epub 2017 May 24.
We previously demonstrated that uridine adenosine tetraphosphate (UpA) induces potent and partially endothelium-dependent relaxation in the healthy porcine coronary microvasculature. We subsequently showed that UpA-induced porcine coronary relaxation was impaired via downregulation of P1 receptors after myocardial infarction. In view of the deleterious effect of metabolic derangement on vascular function, we hypothesized that the coronary vasodilator response to UpA is impaired in metabolic derangement, and that the involvement of purinergic receptor subtypes and endothelium-derived vasoactive factors (EDVFs) is altered. Coronary small arteries, dissected from the apex of healthy swine and swine 6 months after induction of diabetes with streptozotocin and fed a high-fat diet, were mounted on wire myographs. UpA (10-10 M)-induced coronary relaxation was maintained in swine with metabolic derangement compared to normal swine, despite impaired endothelium-dependent relaxation to bradykinin and despite blunted P2X receptor and NO-mediated vasodilator influences of UpA. Moreover, a thromboxane-mediated vasoconstrictor influence was unmasked. In contrast, an increased UpA-mediated vasodilator influence via P2Y receptors was observed, while, in response to UpA, cytochrome P 2C9 switched from producing vasoconstrictor to vasodilator metabolites in swine with metabolic derangement. Coronary vascular expression of A and P2X receptors as well as eNOS, as assessed with real-time PCR, was reduced in swine with metabolic derangement. In conclusion, although the overall coronary vasodilator response to UpA was maintained in swine with metabolic derangement, the involvement of purinergic receptor subtypes and EDVF was markedly altered, revealing compensatory mechanisms among signaling pathways in UpA-mediated coronary vasomotor influence in the early phase of metabolic derangement. Future studies are warranted to investigate the effects of severe metabolic derangement on coronary responses to UpA.
我们之前证明，尿苷腺苷四磷酸（UpA）可诱导健康猪冠状动脉微血管产生强大且部分依赖内皮的舒张反应。随后我们发现，心肌梗死后 P1 受体下调会损害 UpA 诱导的猪冠状动脉舒张反应。鉴于代谢紊乱对血管功能的有害影响，我们假设 UpA 引起的冠状血管舒张反应在代谢紊乱中受损，并且嘌呤能受体亚型和内皮衍生的血管活性因子（EDVFs）的参与也会改变。从健康猪的心脏顶部分离出冠状动脉小动脉，并在诱导糖尿病 6 个月后用链脲佐菌素喂养高脂肪饮食的猪身上进行分离，然后将其安装在电生理记录肌动描记器上。与正常猪相比，代谢紊乱的猪的 UpA（10-10M）诱导的冠状血管舒张反应得以维持，尽管对 bradykinin 的内皮依赖性舒张反应受损，并且 UpA 的 P2X 受体和 NO 介导的血管舒张作用减弱。此外，还揭示了血栓素介导的血管收缩作用。相比之下，观察到通过 P2Y 受体增加了 UpA 介导的血管舒张作用，而在代谢紊乱的猪中，细胞色素 P 2C9 在响应 UpA 时从产生血管收缩代谢物切换为产生血管舒张代谢物。通过实时 PCR 评估，代谢紊乱的猪的冠状血管 A 和 P2X 受体以及 eNOS 的表达减少。总之，尽管代谢紊乱的猪的整体冠状血管对 UpA 的舒张反应得以维持，但嘌呤能受体亚型和 EDVF 的参与发生了明显改变，揭示了代谢紊乱早期 UpA 介导的冠状血管舒缩影响中信号通路之间的代偿机制。需要进一步的研究来调查严重代谢紊乱对 UpA 引起的冠状血管反应的影响。
