Fluvastatin increases prostacyclin and decreases endothelin production by human umbilical vein endothelial cells

Seeger, Harald; Ao, Mueck; Th, Lippert

doi:10.5414/cpp38270

Cited by 37 publications

(25 citation statements)

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“…19,20 In addition, statins increase prostacyclin and decrease endothelin levels, properties that are beneficial in the treatment of PAH. 21 Consistent with this concept, various animal models of PAH have shown beneficial effects of statins on mean pulmonary arterial pressures, right ventricular hypertrophy, endothelial dysfunction, pulmonary vascular remodeling, and inflammation. [7][8][9][10] Although the effect of statins on pulmonary vascular remodeling in animal models of PAH is convincing, only a few clinical trials with small sample sizes have studied the role of statins in patients with PAH.…”

Section: Discussionmentioning

confidence: 85%

A Systematic Review and Meta‐Analysis of Trials Using Statins in Pulmonary Arterial Hypertension

et al. 2016

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Statins improve pulmonary vascular remodeling and right ventricular hypertrophy in animal models of pulmonary arterial hypertension (PAH). However, clinical trials assessing the efficacy of statins in patients with PAH have reported mixed results. In this systematic review and meta-analysis, we assess the efficacy of statins in patients with PAH. We included randomized controlled clinical trials (RCTs) that evaluated the efficacy of statins in patients with PAH. Primary outcomes were mortality and change in 6-minute walk distance (6MWD). Data are presented as odds ratio (OR) and weighted mean difference (WMD), with 95% confidence intervals (CIs), for binary and continuous variables, respectively. We included 4 RCTs of high quality. The mean age of participants was 42 ± 13 years, and 70% were women. The statins used were simvastatin at 40-80 mg in two trials, atorvastatin 10 mg in one trial, and rosuvastatin 10 mg in the other. In the pooled-data analysis, there was no statistically significant improvement in mortality (OR: 0.75 [95% CI: 0.32-1.74]), 6MWD (WMD: −9.27 [95% CI: −27.73 to 9.20]), or cardiac index (WMD: 0.11 [95% CI: −0.04 to 0.27]) with statin therapy when compared to placebo. There was no difference in adverse events leading to withdrawal of therapy between statin and placebo groups. These data suggest that statins are not beneficial in the treatment of PAH. There is a need for large, well-conducted clinical trials assessing the effects of statins in patients with PAH. Future trials should include homogeneous patient populations and should be long-term, eventdriven trials with combined morbidity and mortality end points.Keywords: right ventricle, hemodynamics, vascular remodeling, pulmonary embolism. Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased pulmonary vascular resistance leading to right heart failure and eventually death.1 Pulmonary vasoconstriction, thrombosis, small-vessel remodeling with increased proliferation of vascular smooth muscle cells and endothelial cells, and inflammation contribute to increased pulmonary vascular resistance. 2 Although significant progress has been made in the past 2 decades, PAH, unfortunately, continues to remain a fatal disease, with a 1-year mortality of ∼10%-15%. 3-5 All currently approved therapies for PAH cause pulmonary vasodilatation by targeting one of three pathways: endothelin, nitric oxide, or prostacyclin. 6 There is an unmet need for novel therapies in PAH that can reverse vascular remodeling by targeting pulmonary vascular smooth muscle and endothelial cell proliferation.Statins have pleiotropic effects that include antiproliferative, antithrombotic, antioxidant, and anti-inflammatory properties, making them an attractive option for treatment of PAH. As such, statins have been shown to prevent and reverse pulmonary vascular remodeling in several animal models of PAH by virtue of their proapoptotic and antiproliferative effects on pulmonary artery smooth muscle cells.7-10 Subsequently, based on these ...

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Section: Discussionmentioning

confidence: 85%

A Systematic Review and Meta‐Analysis of Trials Using Statins in Pulmonary Arterial Hypertension

et al. 2016

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“…Both endothelin-1 (21) and endothelin receptor (47) transcription are reduced by statins, which would be expected to attenuate chronic hypoxic pulmonary hypertension. These agents also increase prostacyclin production from both endothelial and vascular smooth muscle cells (9,40). Statins have potent antioxidant effects (26), and given that oxidant stress may be an important mediator of chronic hypoxic pulmonary hypertension (23), as well as acute hypoxic pulmonary vasoconstriction (46), this mechanism could also contribute to the effects of simvastatin on pulmonary vascular remodeling.…”

Section: Discussionmentioning

confidence: 99%

“…For example, statins upregulate endothelial nitric oxide (NO) synthase (eNOS) expression and activity (13), increase prostacyclin (40), and reduce endothelin production by endothelial cells (20). Statins are also potent inhibitors of vascular smooth muscle cell growth (30), a prominent feature of human and experimental pulmonary hypertension (10).…”

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confidence: 99%

Attenuation of chronic hypoxic pulmonary hypertension by simvastatin

Girgis¹,

Li²,

Zhan³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

145

127

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. Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Circ Physiol 285: H938-H945, 2003. First published May 15, 2003 10.1152/ ajpheart.01097.2002The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to improve multiple normal endothelial cell functions and inhibit vascular wall cell proliferation. We hypothesized that one such agent, simvastatin, would attenuate chronic hypoxic pulmonary hypertension. Male adult Sprague-Dawley rats were exposed (14 days) to normoxia (N), normoxia plus once-a-day administered simvastatin (20 mg/kg ip) (NS), hypoxia (10% inspired O 2 fraction) (H), or hypoxia plus simvastatin (HS). Mean pulmonary artery pressure, measured in anesthetized, ventilated rats with an open-chest method, was reduced from 25 Ϯ 2 mmHg in H to 18 Ϯ 1 in HS (P Ͻ 0.001) but did not reach normoxic values (12 Ϯ 1 mmHg). Similarly, right ventricular/left ventricular plus interventricular septal weight was reduced from 0.53 Ϯ 0.02 in the H group to 0.36 Ϯ 0.02 in the HS group (P Ͻ 0.001). The increased hematocrit in H (0.65 Ϯ 0.02) was prevented by simvastatin treatment (0.51 Ϯ 0.01, P Ͻ 0.001). Hematocrit was similar in N versus NS. Alveolar vessel muscularization and medial thickening of vessels 50-200 M in diameter induced by hypoxia were also significantly attenuated in the HS animals. Lung endothelial nitric oxide synthase (eNOS) protein expression in the HS group was less than H (P Ͻ 0.01) but was similar in N versus NS. We conclude that simvastatin treatment potently attenuates chronic hypoxic pulmonary hypertension and polycythemia in rats and inhibits vascular remodeling. Enhancement of lung eNOS expression does not appear to be involved in mediating this effect. pulmonary vascular remodeling; 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition; nitric oxide; polycythemia; small G proteins CHRONIC PULMONARY HYPERTENSION is characterized by a component of abnormal pulmonary vasoconstriction and by structural remodeling of the small pulmonary arteries. Both processes lead to a progressive increase in pulmonary vascular resistance, which, when extreme, culminates in right ventricular (RV) failure and death. The syndrome occurs in diverse clinical settings, including lung disease associated with alveolar hypoxia. Endothelial cell injury-dysfunction is considered to be a key factor in the pathogenesis of pulmonary hypertension (3), leading to increased vascular smooth muscle tone, cell proliferation in the vascular wall, and activation of thrombotic mechanisms, all of which participate in the process of remodeling. Currently available therapies have a beneficial clinical effect yet cannot reverse the disease process. Therefore, the response is variable with considerable morbidity and mortality despite therapy (33). Clearly, there is an urgent need for new therapies.The 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase inhibitors (statins) have been shown to exert numerous effects on vascular wall function, independent of t...

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“…The endothelium is a major effector cell compartment for the pleiotropic effects of statins. Statins increase eNOS activity (32), decrease oxidative stress (33), downregulate expression of TF (34), endothelin-1 (35) and plasminogen activator inhibitor-1 (PAI-1) (36), and upregulate prostacyclin (37), tissue-type plasminogen activator (tPA) (36), and endothelial TM (38,39).…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Ameliorates Radiation Enteropathy Development After Localized, Fractionated Irradiation by a Protein C-Independent Mechanism

Wang

Boerma

et al. 2007

International Journal of Radiation Oncology*Biology*Physics

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Fluvastatin increases prostacyclin and decreases endothelin production by human umbilical vein endothelial cells

Cited by 37 publications

References 0 publications

A Systematic Review and Meta‐Analysis of Trials Using Statins in Pulmonary Arterial Hypertension

A Systematic Review and Meta‐Analysis of Trials Using Statins in Pulmonary Arterial Hypertension

Attenuation of chronic hypoxic pulmonary hypertension by simvastatin

Simvastatin Ameliorates Radiation Enteropathy Development After Localized, Fractionated Irradiation by a Protein C-Independent Mechanism

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