Phosphorylation inactivation of endothelial nitric oxide synthesis in pulmonary arterial hypertension (original) (raw)
Related papers
Variable expression of endothelial NO synthase in three forms of rat pulmonary hypertension
American Journal of …, 1999
Endothelial nitric oxide (NO) synthase (eNOS) mRNA and protein and NO production are increased in hypoxia-induced hypertensive rat lungs, but it is uncertain whether eNOS gene expression and activity are increased in other forms of rat pulmonary hypertension. To investigate these questions, we measured eNOS mRNA and protein, eNOS immunohistochemical localization, perfusate NO product levels, and NO-mediated suppression of resting vascular tone in chronically hypoxic (3-4 wk at barometric pressure of 410 mmHg), monocrotaline-treated (4 wk after 60 mg/kg), and fawn-hooded (6-9 mo old) rats. eNOS mRNA levels (Northern blot) were greater in hypoxic and monocrotaline-treated lungs (130 and 125% of control lungs, respectively; P Ͻ 0.05) but not in fawn-hooded lungs. Western blotting indicated that eNOS protein levels increased to 300 Ϯ 46% of control levels in hypoxic lungs (P Ͻ 0.05) but were decreased by 50 Ϯ 5 and 60 Ϯ 11%, respectively, in monocrotaline-treated and fawn-hooded lungs (P Ͻ 0.05). Immunostaining showed prominent eNOS expression in small neomuscularized arterioles in all groups, whereas perfusate NO product levels increased in chronically hypoxic lungs (3.4 Ϯ 1.4 µM; P Ͻ 0.05) but not in either monocrotaline-treated (0.7 Ϯ 0.3 µM) or fawn-hooded (0.45 Ϯ 0.1 µM) lungs vs. normotensive lungs (0.12 Ϯ 0.07 µM). All hypertensive lungs had increased baseline perfusion pressure in response to nitro-L-arginine but not to the inducible NOS inhibitor aminoguanidine. These results indicate that even though NO activity suppresses resting vascular tone in pulmonary hypertension, there are differences among the groups regarding eNOS gene expression and NO production. A better understanding of eNOS gene expression and activity in these models may provide insights into the regulation of this vasodilator system in various forms of human pulmonary hypertension.
The Nitric Oxide Pathway in Pulmonary Vascular Disease
The American journal of cardiology, 2017
Nitric oxide is an endogenous pulmonary vasodilator that is synthesized from L-arginine in pulmonary vascular endothelial cells by nitric oxide synthase and diffuses to adjacent vascular smooth muscle cells where it activates soluble guanylyl cyclase. This enzyme converts GTP to cGMP which activates cGMP dependent protein kinase leading to a series of events that decrease intracellular calcium and reduce vascular muscle tone. Nitric oxide is an important mediator of pulmonary vascular tone and vascular remodeling. A number of studies suggest that the bioavailability of nitric oxide is reduced in patients with pulmonary vascular disease and that augmentation of the nitric oxide/cGMP pathway may be an effective strategy for treatment. Several medications that target nitric oxide/cGMP signaling are now available for the treatment of pulmonary hypertension. This review explores the history of nitiric oxide research, describes the major NO synthetic and signaling pathways and discusses a...
Reduced Hypoxic Pulmonary Vascular Remodeling by Nitric Oxide From the Endothelium
Hypertension, 2001
We examined whether overproduction of endogenous nitric oxide (NO) can prevent hypoxia-induced pulmonary hypertension and vascular remodeling by using endothelial NO-overexpressing (eNOS-Tg) mice. Male eNOS-Tg mice and their littermates (wild-type, WT) were maintained in normoxic or 10% hypoxic condition for 3 weeks. In normoxia, eNOS protein levels, Ca 2ϩ -dependent NOS activity, and cGMP levels in the lung of eNOS-Tg mice were higher than those of WT mice. Activity of eNOS and cGMP production in the lung did not change significantly by hypoxic exposure in either genotype. Chronic hypoxia did not induce iNOS expression nor increase its activity in either genotype. Plasma and lung endothelin-1 levels were increased by chronic hypoxia, but these levels were not significantly different between the 2 genotypes. In hemodynamic analysis, right ventricular systolic pressure (RVSP) in eNOS-Tg mice was similar to that in WT mice in normoxia. Chronic hypoxia increased RVSP and induced right ventricular hypertrophy in both genotypes; however, the degrees of these increases were significantly smaller in eNOS-Tg mice. Histological examination revealed that hypoxic mice showed medial wall thickening in pulmonary arteries. However, the increase of the wall thickening in small arteries (diameter Ͻ80 m) by chronic hypoxia was inhibited in eNOS-Tg mice. Furthermore, muscularization of small arterioles was significantly attenuated in eNOS-Tg mice. Thus, we demonstrated directly that overproduction of eNOS-derived NO can inhibit not only the increase in RVSP associated with pulmonary hypertension but also remodeling of the pulmonary vasculature and right ventricular hypertrophy induced by chronic hypoxia. (Hypertension. 2001;37:322-327.)
Nitric oxide and pulmonary arterial pressures in pulmonary hypertension
Free Radical Biology and Medicine, 2004
Decreased production of vasodilator substances such as nitric oxide (NO) has been proposed as important in development of pulmonary arterial hypertension (PAH). We hypothesize that NO measured over time serves as a non invasive marker of severity of PAH and response to therapy. We prospectively and serially measured exhaled NO and carbon monoxide (CO), a vasodilator and anti-inflammatory product of heme oxygenases, in 17 PAH patients in conjunction with hemodynamic parameters over 2 years. Although pulmonary artery pressures and NO were similar in all patients at entry to the study, NO increased in the 12 individuals who survived to complete the study, and correlated with change in pulmonary artery pressures. In contrast, CO did not change or correlate with hemodynamic parameters. Investigation of NO-oxidant reaction products in PAH in comparison to controls suggests that NO synthesis is impaired in the lung and that reactive oxygen species may be involved in the pathophysiology of pulmonary hypertension. Endogenous NO is inversely related to pulmonary artery pressure in PAH, with successful therapy of PAH associated with increase in NO. D
Nitric Oxide Deficiency in Pulmonary Hypertension: Pathobiology and Implications for Therapy
Pulmonary Circulation, 2013
Nitric oxide (NO) is a diffusible gas with diverse roles in human physiology and disease. Significant progress in the understanding of its biological effects has taken place in recent years. This has led to a better understanding of the pathobiology of pulmonary hypertension (PH) and the development of new therapies. This article provides an overview of the NO physiology and its role in the pathobiology of lung diseases, particularly PH. We also discuss current and emerging specific treatments that target NO signaling pathways in PH.
British Journal of Pharmacology, 2003
1 Chronic hypoxia (CH) increases lung tissue expression of all types of nitric oxide synthase (NOS) in the rat. However, it remains unknown whether CH-induced changes in functional and histological NOS distributions are correlated in rat small pulmonary arteries. 2 We measured the effects of NOS inhibitors on the internal diameters (ID) of muscular (MPA) and elastic (EPA) pulmonary arteries (100 -700 mm ID) using an X-ray television system on anaesthetized rats. We also conducted NOS immunohistochemical localization on the same vessels. 3 Nonselective NOS inhibitors induced ID reductions in almost all MPA of CH rats (mean reduction, 3673%), as compared to B60% of control rat MPA (mean, 1072%). The inhibitors reduced the ID of almost all EPA with similar mean values (B26%) in both CH and control rats. On the other hand, inducible NOS (iNOS)-selective inhibitors caused ID reductions in B60% of CH rat MPA (mean, 1573%), but did so in only B20% of control rat MPA (mean, 272%). This inhibition caused only a small reduction (mean, B4%) in both CH and control rat EPA. A neuronal NOSselective inhibitor had no effect. 4 The percentage of endothelial NOS (eNOS)-positive vessels was B96% in both MPA and EPA from CH rats, whereas it was 51 and 91% in control MPA and EPA, respectively. The percentage for iNOS was B60% in both MPA and EPA from CH rats, but was only B8% in both arteries from control rats. 5 The data indicate that in CH rats, both functional and histological upregulation of eNOS extensively occurs within MPA. iNOS protein increases sporadically among parallel-arranged branches in both MPA and EPA, but its vasodilatory effect is predominantly observed in MPA. Such NOS upregulation may serve to attenuate hypoxic vasoconstriction, which occurs primarily in MPA and inhibit the progress of pulmonary hypertension.
eNOS-deficient mice show reduced pulmonary vascular proliferation and remodeling to chronic hypoxia
American journal of physiology. Lung cellular and molecular physiology, 2000
Pulmonary hypertension is characterized by structural and morphological changes to the lung vasculature. To determine the potential role of nitric oxide in the vascular remodeling induced by hypoxia, we exposed wild-type [WT(+/+)] and endothelial nitric oxide synthase (eNOS)-deficient [(-/-)] mice to normoxia or hypoxia (10% O(2)) for 2, 4, and 6 days or for 3 wk. Smooth muscle alpha-actin and von Willebrand factor immunohistochemistry revealed significantly less muscularization of small vessels in hypoxic eNOS(-/-) mouse lungs than in WT(+/+) mouse lungs at early time points, a finding that correlated with decreases in proliferating vascular cells (5-bromo-2'-deoxyuridine positive) at 4 and 6 days of hypoxia in the eNOS(-/-) mice. After 3 wk of hypoxia, both mouse types exhibited similar percentages of muscularized small vessels; however, only the WT(+/+) mice exhibited an increase in the percentage of fully muscularized vessels and increased vessel wall thickness. eNOS protein...
The FASEB Journal, 2004
Pulmonary arterial hypertension (PAH), a fatal disease of unknown etiology characterized by impaired regulation of pulmonary hemodynamics and vascular growth, is associated with low levels of pulmonary nitric oxide (NO). Based upon its critical role in mediating vasodilation and cell growth, decrease of NO has been implicated in the pathogenesis of PAH. We evaluated mechanisms for low NO and pulmonary hypertension, including NO synthases (NOS) and factors regulating NOS activity, i.e. the substrate arginine, arginase expression and activity, and endogenous inhibitors of NOS in patients with PAH and healthy controls. PAH lungs had normal NOS I-III expression, but substrate arginine levels were inversely related to pulmonary artery pressures. Activity of arginase, an enzyme that regulates NO biosynthesis through effects on arginine, was higher in PAH serum than in controls, with high-level arginase expression localized by immunostaining to pulmonary endothelial cells. Further, pulmonary artery endothelial cells derived from PAH lung had higher arginase II expression and produced lower NO than control cells in vitro. Thus, substrate availability affects NOS activity and vasodilation, implicating arginase II and alterations in arginine metabolic pathways in the pathophysiology of PAH.
Role of inhibition of nitric oxide production in monocrotaline-induced pulmonary hypertension
Journal of Applied Physiology, 1997
induced pulmonary hypertension (PH) is associated with impaired endothelium-dependent nitric oxide (NO)-mediated relaxation. To examine the role of NO in PH, Sprague-Dawley rats were given a single subcutaneous injection of normal saline [control (C)], 80 mg/kg MCT, or the same dose of MCT and a continuous subcutaneous infusion of 2 mg • kg 21 • day 21 of molsidomine, a NO prodrug (MCT1MD). Two weeks later, plasma NO 3 2 levels, pulmonary arterial pressure (Ppa), ratio of right-to-left ventricular weights (RV/LV) to assess right ventricular hypertrophy, and pulmonary histology were evaluated. The plasma NO 3 2 level in the MCT group was reduced to 9.2 6 1.5 µM (n 5 12) vs. C level of 17.7 6 1.8 µM (n 5 8; P , 0.02). In the MCT1MD group, plasma NO 3 2 level was 12.3 6 2.0 µM (n 5 8). Ppa and RV/LV in the MCT group were increased compared with C [Ppa, 34 6 3.4 mmHg (n 5 6) vs. 19 6 0.8 mmHg (n 5 8) and 0.41 6 0.01 (n 5 9) vs. 0.25 6 0.008 (n 5 8), respectively; P , 0.001]. In the MCT1MD group, Ppa and RV/LV were not different when compared with C [19 6 0.5 mmHg (n 5 5) and 0.27 6 0.01 (n 5 9), respectively; P , 0.001 vs. MCT]. Medial wall thickness of lung vessels in the MCT group was increased compared with C [31 6 1.5% (n 5 9) vs. 13 6 0.66% (n 5 9); P , 0.001], and MD partially prevented MCT-induced pulmonary vascular remodeling [22 6 1.2% (n 5 11); P , 0.001 vs. MCT and C]. These results indicate that a defect in the availability of bioactive NO may play an important role in the pathogenesis of MCT-induced PH. molsidomine; pulmonary vascular remodeling ENDOTHELIAL DYSFUNCTION is thought to underlie various clinical and experimental forms of pulmonary hypertension. The absence of a relaxation response to nitroglycerin in pulmonary microvessels in vitro is reported to be associated with a high mortality rate in children with congenital heart defect and pulmonary hypertension. Reduced nitric oxide (NO) generation in the lungs has been shown in this clinical group (8, 23). Impaired endothelium-dependent NO-mediated relaxation has been shown in isolated pulmonary arteries (PA) from humans suffering from Eisenmenger syndrome (9). However, there are conflicting reports about NO production in experimental models of pulmonary hypertension. There have been findings suggestive of increased NO production in chronic hypoxia-induced pulmonary hypertension in rats (16, 36) and monocrotaline (MCT)-induced pulmonary hypertension (20),