(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Hypertension--Pulmonary

Statins are Hydroxymethylglutaryl-coenzyme A reductase inhibitors, which are typically used to lower blood cholesterol. Additional beneficial effects, including improvement to pulmonary arterial hypertension (PAH), have also been confirmed. However, the mechanisms underlying this improvement have not yet been clarified. The present study was conducted to determine if fluvastatin was protective against experimental PAH development and to investigate the potential effects of fluvastatin on caveolin‑1 (cav‑1) expression. Rats were randomized to either receive a single subcutaneous injection of monocrotaline (MCT; 60 mg/kg; MCT group) or a single subcutaneous injection of MCT (60 mg/kg) followed by an oral gavage of fluvastatin (10 mg/kg) once daily until day 42 (M + F group). Rats in the MCT group received an equivalent volume of saline following the MCT injection. Six additional rats were given an equivalent volume of saline throughout as a control measure. PAH associated variables and cav‑1 protein expression were measured in each group at various times during the experimental period. Hemodynamic and morphometric analysis revealed that M + F rats developed moderate, delayed PAH. Cav‑1 western blot analysis demonstrated that cav‑1 expression was not significantly different in fluvastatin treated rats; however, MCT injured rats given saline had markedly reduced cav‑1 expression. It was concluded that fluvastatin may protect against PAH development and ameliorate MCT induced inhibition of cav‑1 expression in rats.

Topics: Administration, Oral; Animals; Anticholesteremic Agents; Antihypertensive Agents; Caveolin 1; Drug Administration Schedule; Fatty Acids, Monounsaturated; Fluvastatin; Gene Expression Regulation; Hemodynamics; Hypertension, Pulmonary; Indoles; Injections, Subcutaneous; Male; Monocrotaline; Rats; Rats, Wistar; Signal Transduction

Hypoxic pulmonary hypertension is a worldwide public health problem. Statins attenuate hypoxic pulmonary hypertension in animal models, but the mechanism of action and applicability of these results to human treatment are not established. In hypoxic models, pulmonary artery fibroblast proliferation contributes substantially to pulmonary vascular remodeling. We previously showed that acute hypoxic pulmonary adventitial fibroblast proliferation can be selectively inhibited by statins and p38 mitogen-activated protein (MAP) kinase inhibitors. Here we used complementary chronic hypoxic and acute hypoxic coculture models to obtain necessary preclinical information regarding the utility of fluvastatin in the treatment of chronic hypoxic pulmonary hypertension. The effects of fluvastatin, cholesterol pathway intermediates, and related inhibitors on hypoxic adventitial fibroblast proliferation, p38 MAP kinase phosphorylation, and pulmonary artery smooth muscle cell proliferation were determined, using complementary chronic hypoxic rat and acute hypoxic bovine cell models. Fluvastatin reversed the proliferative phenotypic switch in adventitial fibroblasts from chronic hypoxic animals. This effect was circulation-specific, and implicated a Rac1-p38 MAP kinase signaling pathway. Coculture and conditioned media experiments also implicated this statin-sensitive signaling pathway in the release of pulmonary artery smooth muscle cell mitogens by hypoxic pulmonary adventitial fibroblasts. Treprostinil, sildenafil, and bosentan exerted no effect on the hypoxic fibroblast phenotype. Phenotypic changes (increased proliferation and mitogen release) in pulmonary artery fibroblasts during chronic hypoxia are dependent on a Rac1-p38 MAP kinase signaling pathway. The inhibition of these phenotypic changes with fluvastatin may be therapeutically relevant in high-altitude residents and in patients with hypoxic lung disease.

Topics: Animals; Cattle; Cell Hypoxia; Cell Proliferation; Cells, Cultured; Cholesterol; Fatty Acids, Monounsaturated; Fibroblasts; Fluvastatin; Hypertension, Pulmonary; Hypoxia; Indoles; Lung; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; p38 Mitogen-Activated Protein Kinases; Phenotype; Phosphorylation; Pulmonary Artery; Rats; Rats, Wistar; Signal Transduction

We investigated the effects of fluvastatin on hypoxia-induced (1 to 3 weeks, 10% O2) pulmonary hypertension with focus on endothelial nitric oxide synthase (eNOS) activity.. 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 Ser1177-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.. These results suggest that the fluvastatin exerts beneficial effects on chronic hypoxia-induced pulmonary hypertension by protecting against the eNOS activity at the post-transcriptional level.

Topics: Animals; Blood Pressure; Caveolin 1; Chronic Disease; Cyclic GMP; Electrocardiography; Endothelium, Vascular; Fatty Acids, Monounsaturated; Fluvastatin; HSP90 Heat-Shock Proteins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Pulmonary; Hypoxia; Indoles; Myocardium; Nitric Oxide Synthase Type III; Organ Size; Phosphorylation; Proto-Oncogene Proteins c-akt; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Vasodilation; Ventricular Function, Right