Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Oxid Med Cell Longev. 2021 Jan 28;2021:6621232. doi: 10.1155/2021/6621232. eCollection 2021.
Pulmonary hypertension (PH) is a progressive and life-threatening chronic disease in which increased pulmonary artery pressure (PAP) and pulmonary vasculature remodeling are prevalent. Inhaled nitric oxide (NO) has been used in newborns to decrease PAP in the clinic; however, the effects of NO endogenous derivatives, S-nitrosothiols (SNO), on PH are still unknown. We have reported that S-nitroso-L-cysteine (CSNO), one of the endogenous derivatives of NO, inhibited RhoA activity through oxidative nitrosation of its C16/20 residues, which may be beneficial for both vasodilation and remodeling. In this study, we presented data to show that inhaled CSNO attenuated PAP in the monocrotaline- (MCT-) induced PH rats and, moreover, improved right ventricular (RV) hypertrophy and fibrosis induced by RV overloaded pressure. In addition, aerosolized CSNO significantly inhibited the hyperactivation of signal transducers and activators of transduction 3 (STAT3) and extracellular regulated protein kinases (ERK) pathways in the lung of MCT-induced rats. CSNO also regulated the expression of smooth muscle contractile protein and improved aberrant endoplasmic reticulum (ER) stress and mitophagy in lung tissues following MCT induction. On the other hand, CSNO inhibited reactive oxygen species (ROS) production in vitro, which is induced by angiotensin II (AngII) as well as interleukin 6 (IL-6). In addition, CSNO inhibited excessive ER stress and mitophagy induced by AngII and IL-6 in vitro; finally, STAT3 and ERK phosphorylation was inhibited by CSNO in a concentration-dependent manner. Taken together, CSNO led to pulmonary artery relaxation and regulated pulmonary circulation remodeling through anti-ROS and anti-inflammatory pathways and may be used as a therapeutic option for PH treatment.
肺动脉高压（PH）是一种进行性的、危及生命的慢性疾病，其特征是肺动脉压（PAP）升高和肺血管重构。吸入一氧化氮（NO）已在临床上用于降低新生儿的 PAP；然而，NO 内源性衍生物 S-亚硝基硫醇（SNO）对 PH 的影响尚不清楚。我们曾报道，NO 的一种内源性衍生物 S-亚硝基-L-半胱氨酸（CSNO）通过其 C16/20 残基的氧化亚硝化抑制 RhoA 活性，这可能对血管舒张和重构都有益。在这项研究中，我们提供的数据表明，吸入 CSNO 可减轻野百合碱（MCT）诱导的 PH 大鼠的 PAP，并且改善了 RV 超负荷压力引起的右心室（RV）肥大和纤维化。此外，气溶胶 CSNO 可显著抑制 MCT 诱导的大鼠肺部信号转导和转录激活因子 3（STAT3）和细胞外调节蛋白激酶（ERK）途径的过度激活。CSNO 还调节平滑肌收缩蛋白的表达，并改善 MCT 诱导后的肺组织中异常的内质网（ER）应激和自噬。另一方面，CSNO 抑制了血管紧张素 II（AngII）和白细胞介素 6（IL-6）诱导的体外活性氧（ROS）的产生。此外，CSNO 抑制了 AngII 和 IL-6 诱导的过度 ER 应激和自噬；最后，CSNO 以浓度依赖性方式抑制 STAT3 和 ERK 磷酸化。总之，CSNO 通过抗 ROS 和抗炎途径导致肺动脉松弛，并调节肺循环重构，可能可作为 PH 治疗的一种治疗选择。
