Abstract
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.
Highlights
Pulmonary hypertension (PH) is a life-threatening cardiopulmonary disease characterized by pulmonary artery vascular contraction and remodeling, possibly due to pulmonary vascular endothelial cell dysfunction, smooth muscle cell proliferation, and perivascular inflammation [1, 2]
When diseased animals were treated with CSNO, the mean pulmonary artery pressure (mPAP) decreased significantly compared to the nontreatment group, with the trend being more effective in the early treatment group (Figures 1(a) and 1(b))
To further confirm the effect of CSNO on hemodynamic changes in pulmonary arteries and avoid potential bias resulting from a different baseline, we calculated pulmonary vascular resistance (PVR) in different groups (Figure 1(c))
Summary
Pulmonary hypertension (PH) is a life-threatening cardiopulmonary disease characterized by pulmonary artery vascular contraction and remodeling, possibly due to pulmonary vascular endothelial cell dysfunction, smooth muscle cell proliferation, and perivascular inflammation [1, 2]. We reported that CSNO can transport NO equivalents into intact vascular cells and regulate constriction of vascular smooth muscle cells by Snitrosylation [3, 4], suggesting a role of SNO in the pathogenesis of pulmonary hypertension and its treatment. P-STAT3 and p-ERK both contribute to the smooth muscle cell (SMC) phenotype switch, which was associated with the progression of experimental occlusive pulmonary vascular disease [6]. We reported that CSNO regulated constriction of vascular smooth muscle cells by oxidative nitrosation of RhoA, and CSNO caused Keap thiol modification, which activated the antioxidant response element (ARE), leading to transcriptional upregulation of cytoprotective and antioxidant genes. We investigated the effect of CSNO on pulmonary vessel constriction and remodeling and explored the underlying mechanisms through which CSNO attenuated mPAP, alternated pulmonary vascular remodeling, and improved RV hypertrophy and PH development
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