Department of Pharmacology and Personalised Medicine, MeHNS, FHML, Maastricht University, Maastricht, The Netherlands.
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
Sci Rep. 2020 Jun 19;10(1):10012. doi: 10.1038/s41598-020-66639-w.
Nitric oxide (NO)-cyclic GMP (cGMP) signaling is a vasoprotective pathway therapeutically targeted, for example, in pulmonary hypertension. Its dysregulation in disease is incompletely understood. Here we show in pulmonary artery endothelial cells that feedback inhibition by NO of the NO receptor, the cGMP forming soluble guanylate cyclase (sGC), may contribute to this. Both endogenous NO from endothelial NO synthase and exogenous NO from NO donor compounds decreased sGC protein and activity. This effect was not mediated by cGMP as the NO-independent sGC stimulator, or direct activation of cGMP-dependent protein kinase did not mimic it. Thiol-sensitive mechanisms were also not involved as the thiol-reducing agent N-acetyl-L-cysteine did not prevent this feedback. Instead, both in-vitro and in-vivo and in health and acute respiratory lung disease, chronically elevated NO led to the inactivation and degradation of sGC while leaving the heme-free isoform, apo-sGC, intact or even increasing its levels. Thus, NO regulates sGC in a bimodal manner, acutely stimulating and chronically inhibiting, as part of self-limiting direct feedback that is cGMP independent. In high NO disease conditions, this is aggravated but can be functionally recovered in a mechanism-based manner by apo-sGC activators that re-establish cGMP formation.
一氧化氮（NO）-环鸟苷酸（cGMP）信号转导是一种血管保护途径，例如在肺动脉高压中被靶向治疗。但其在疾病中的失调机制尚不完全清楚。在这里，我们在肺动脉内皮细胞中表明，NO 对其受体（形成 cGMP 的可溶性鸟苷酸环化酶[sGC]）的反馈抑制作用可能促成了这一点。内皮型一氧化氮合酶产生的内源性 NO 和 NO 供体化合物产生的外源性 NO 均降低了 sGC 蛋白和活性。这种效应不是由 cGMP 介导的，因为 NO 非依赖性 sGC 刺激剂或直接激活 cGMP 依赖性蛋白激酶并不能模拟这种效应。巯基敏感机制也不参与其中，因为巯基还原剂 N-乙酰-L-半胱氨酸不能阻止这种反馈。相反，在体内和体外以及在健康和急性呼吸肺部疾病中，慢性升高的 NO 导致 sGC 失活和降解，而游离血红素同工型，即 apo-sGC，保持完整甚至增加其水平。因此，NO 以双模态方式调节 sGC，急性刺激和慢性抑制，作为自我限制的直接反馈的一部分，该反馈与 cGMP 无关。在高 NO 疾病条件下，这种情况会加剧，但 apo-sGC 激活剂可以通过一种基于机制的方式恢复 cGMP 形成，从而在功能上得到恢复。
