Department Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto- University of Sao Paulo Av. Do Cafe SN, Brazil.
Department of Pharmacology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Curr Pharm Des. 2020;26(30):3748-3759. doi: 10.2174/1381612826666200519114442.
Endothelial dysfunction and consequent vasoconstriction are a common condition in patients with hypertension and other cardiovascular diseases. Endothelial cells produce and release vasodilator substances that play a pivotal role in normal vascular tone. The mechanisms underlying endothelial dysfunction are multifactorial. However, enhanced reactive oxygen species (ROS) production and consequent vasoconstriction instead of endothelium-derived relaxant generation and consequent vasodilatation contribute to this dysfunction considerably. The main targets of the drugs that are currently used to treat vascular diseases concerning enzyme activities and protein functions that are impaired by endothelial nitric oxide synthase (eNOS) uncoupling and ROS production. Nitric oxide (NO) bioavailability can decrease due to deficient NO production by eNOS and/or NO release to vascular smooth muscle cells, which impairs endothelial function. Considering the NO cellular mechanisms, tackling the issue of eNOS uncoupling could avoid endothelial dysfunction: provision of the enzyme cofactor tetrahydrobiopterin (BH4) should elicit NO release from NO donors, to activate soluble guanylyl cyclase. This should increase cyclic guanosine-monophosphate (cGMP) generation and inhibit phosphodiesterases (especially PDE5) that selectively degrade cGMP. Consequently, protein kinase-G should be activated, and K+ channels should be phosphorylated and activated, which is crucial for cell membrane hyperpolarization and vasodilation and/or inhibition of ROS production. The present review summarizes the current concepts about the vascular cellular mechanisms that underlie endothelial dysfunction and which could be the target of drugs for the treatment of patients with cardiovascular disease.
内皮功能障碍和随之而来的血管收缩是高血压和其他心血管疾病患者的常见病症。内皮细胞产生和释放血管舒张物质，在正常血管张力中起着关键作用。内皮功能障碍的机制是多因素的。然而，增强的活性氧（ROS）产生和随之而来的血管收缩，而不是内皮衍生的松弛物质的产生和随之而来的血管舒张，对这种功能障碍有很大的贡献。目前用于治疗血管疾病的药物的主要靶点是酶活性和蛋白质功能，这些靶点受到内皮型一氧化氮合酶（eNOS）解偶联和 ROS 产生的损害。由于 eNOS 产生的 NO 减少和/或 NO 释放到血管平滑肌细胞减少，导致 NO 生物利用度降低，从而损害内皮功能。考虑到 NO 的细胞机制，解决 eNOS 解偶联的问题可以避免内皮功能障碍：提供酶辅助因子四氢生物蝶呤（BH4）应该从 NO 供体中释放 NO，以激活可溶性鸟苷酸环化酶。这应该增加环鸟苷酸（cGMP）的生成，并抑制磷酸二酯酶（特别是 PDE5），它们选择性地降解 cGMP。因此，蛋白激酶-G 应该被激活，K+通道应该被磷酸化和激活，这对于细胞膜超极化和血管舒张以及/或抑制 ROS 产生至关重要。本综述总结了目前关于内皮功能障碍的血管细胞机制的概念，这些机制可能是治疗心血管疾病患者的药物的靶点。
