Statin Protects Endothelial Nitric Oxide Synthase Activity in Hypoxia-Induced Pulmonary Hypertension

Abstract

Objective-We investigated the effects of fluvastatin on hypoxia-induced (1 to 3 weeks, 10% O 2 ) pulmonary hypertension with focus on endothelial nitric oxide synthase (eNOS) activity. Methods and Results-Oral fluvastatin treatment (1 mg/kg daily) prevented the causing and progression of pulmonary hypertension as determined by the right ventricular pressure, right ventricular hypertrophy, and muscularization of pulmonary artery. We also revealed that fluvastatin treatments prevented the hypoxia-induced decrease in cGMP production in the rat lung and restored the endothelium-dependent relaxation in the pulmonary artery. We revealed that this beneficial effect was not dependent on the increase in eNOS mRNA or protein expression, but was dependent on the inhibition of the eNOS-tight coupling with caveolin-1, the eNOS dissociation from heat shock protein 90, and the decrease in eNOS Ser 1177 -phosphorylation induced by hypoxia. Furthermore, in a whole-mount immunostaining the hypoxia-induced eNOS protein condensation with caveolin-1 of pulmonary endothelial cells was restored by the fluvastatin-treatment. Key Words: endothelial nitric oxide synthase Ⅲ fluvastatin Ⅲ hypoxia H ypoxia commonly occurs in patients with cardiopulmonary disease and in normal individuals at high altitudes. Chronic hypoxia causes sustained pulmonary hypertension, which is characterized by elevated pulmonary arterial pressure, in association with right ventricular hypertrophy, polycythemia, and pulmonary vascular muscularization. Various forms of pulmonary hypertension pose a significant medical problem and the current options for effective prevention and therapy are limited. 1,2 There is evidence that endothelial dysfunction is intimately involved in the onset and progression of pulmonary hypertension through abnormalities in the production, release, or degradation of endothelium-derived factors, primarily nitric oxide (NO) and endothelin-1. 3,4 In fact, endothelial NO synthase (eNOS) is a candidate gene for vascular genetherapy in pulmonary hypertension. 5 eNOS activity is regulated by a variety of factors such as eNOS-caveolin-1 and eNOS-heat shock protein 90 (HSP90) interactions, 6,7 and eNOS Ser 1177 -phosphorylation by serine/threonine kinase Akt. 6,8 In a previous study, we clarified the mechanisms responsible for the impairment of endothelium-dependent NO production at the eNOS post-transcriptional level in pulmonary hypertension using pulmonary arteries isolated from hypoxia-induced pulmonary hypertensive rats. 9 Notably, the level of eNOS Ser 1177 -phosphorylation, which is an index of eNOS activation, was decreased in hypoxic pulmonary arteries, and that may be mediated by the tight coupling between eNOS and caveolin-1. Conclusion-TheseStatins, 3-hydroxyl-3-methylglutaryl coenzyme A (CoA) (3-hydroxy-3-methylglutaryl [HMG]-CoA) reductase inhibitors, have been developed as lipid-lowering drugs. 10 However, recent experiments and clinical trials have demonstrated that statins also exert vasculoprotective effects independent of their c...

Simvastatin as a Treatment for Pulmonary Hypertension Trial

“…Evidence of potential therapeutic benefit from this drug class comes from a series of animal studies but there are no robust data from studies in patients (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Because the response of the RV to the increased afterload in PAH is an important determinant of patient outcome (18)(19)(20)(21), this study examined prospectively the effect of simvastatin on RV mass and function in patients with PAH.…”

“…This spectrum of activity arises from the inhibition of isoprenoids (geranylgeranylpyrophosphate and farnesylpyrophosphate), which are essential for the post-translational isoprenylation of Rho and Ras family GTPases. Statins, in particular simvastatin, have been reported to attenuate the development of pulmonary hypertension in a number of experimental animal models (4)(5)(6)(7)(8)(9)(10)(11)(12) and to regress established pulmonary hypertension and vascular remodeling induced by either pneumonectomy and monocrotaline treatment (13) or chronic hypoxia (14). There is evidence that this is achieved through increased apoptosis as well as reduced proliferation of smooth muscle cells in obstructive vascular lesions.…”

“…There is evidence that this is achieved through increased apoptosis as well as reduced proliferation of smooth muscle cells in obstructive vascular lesions. Of interest, not all studies report a reduction in pulmonary artery pressure (12,15,16), but a reduction in right ventricular (RV) hypertrophy appears to be a consistent finding (4)(5)(6)(7)(8)(9)(12)(13)(14)(15)(16).…”

Pathogenesis of pulmonary hypertension: a case for caveolin-1 and cell membrane integrity

“…During hypoxia, caveolin-1 forms a tight complex with eNOS, resulting in the dysfunction of both molecules, as evidenced by low bioavailability of NO and the activation of PY-STAT3 and PDGF signaling pathways (122a) [reviewed in Mathew (81) and Murata et al (88)]. Interestingly, the disruption of the eNOS/caveolin-1 complex with statin treatment improves functions of both molecules, resulting in the reversal of PH (89). In hypoxia-induced PH, vasoconstriction may have an important role.…”

Chronic pulmonary hypertension and nitric oxide

“…Таким ингибитором является сим вастатин, который оказался способным понизить гипоксическую легочную гипертонию и ремодели рование легочных сосудов [31], не меняя экспрессию eNOS. Последующие исследования показали, что введение другого препарата этой серии -флуваста тина -уменьшает степень повышения систоличес кого давления в правом желудочке и АД в легочных сосудах, а также их ремоделирования при легочной гипертонии, вызванной длительной гипоксией [32]. Механизм этих эффектов, вызываемых указанными ингибиторами, состоит в активации eNOS путем разрушения связи ее с кавеолином 1, что увеличива ет синтез NO.…”