Attenuation of chronic hypoxic pulmonary hypertension by simvastatin.

The 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 O2 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 +/- 2 mmHg in H to 18 +/- 1 in HS (P < 0.001) but did not reach normoxic values (12 +/- 1 mmHg). Similarly, right ventricular/left ventricular plus interventricular septal weight was reduced from 0.53 +/- 0.02 in the H group to 0.36 +/- 0.02 in the HS group (P < 0.001). The increased hematocrit in H (0.65 +/- 0.02) was prevented by simvastatin treatment (0.51 +/- 0.01, P < 0.001). Hematocrit was similar in N versus NS. Alveolar vessel muscularization and medial thickening of vessels 50-200 microM 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 < 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.

[1]  J. Herget,et al.  Role of nitric oxide in the pathogenesis of chronic pulmonary hypertension. , 2000, Physiological reviews.

[2]  M. Moskowitz,et al.  Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice. , 2001, Stroke.

[3]  R. Johns,et al.  eNOS expression is not altered in pulmonary vascular remodeling due to increased pulmonary blood flow. , 1998, American journal of physiology. Lung cellular and molecular physiology.

[4]  U. Laufs,et al.  3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitors Attenuate Vascular Smooth Muscle Proliferation by Preventing Rho GTPase-induced Down-regulation of p27 Kip1 * , 1999, The Journal of Biological Chemistry.

[5]  G. Berry,et al.  Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. , 2002, American journal of respiratory and critical care medicine.

[6]  M. Arzt,et al.  Effects of ET-A receptor blockade on eNOS gene expression in chronic hypoxic rat lungs. , 2003, Journal of applied physiology.

[7]  U. Laufs,et al.  Inhibition of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Blocks Hypoxia-mediated Down-regulation of Endothelial Nitric Oxide Synthase* , 1997, The Journal of Biological Chemistry.

[8]  O. Miura,et al.  Rac is activated by erythropoietin or interleukin-3 and is involved in activation of the Erk signaling pathway , 2002, Oncogene.

[9]  T. Murata,et al.  Decreased Endothelial Nitric-oxide Synthase (eNOS) Activity Resulting from Abnormal Interaction between eNOS and Its Regulatory Proteins in Hypoxia-induced Pulmonary Hypertension* , 2002, The Journal of Biological Chemistry.

[10]  M. Herrera,et al.  Cardiovascular effects of lovastatin in normotensive and spontaneously hypertensive rats. , 1998, General pharmacology.

[11]  K. Kaibuchi,et al.  Small GTP-binding proteins. , 1992, International review of cytology.

[12]  R. Naeye.  Polycythemia and hypoxia. Individual effects on heart and pulmonary arteries. , 1967, The American journal of pathology.

[13]  D. Pérez-Sala,et al.  Involvement of Rho GTPases in the Transcriptional Inhibition of Preproendothelin-1 Gene Expression by Simvastatin in Vascular Endothelial Cells , 2000, Circulation research.

[14]  A. Evans,et al.  Inhibition of sustained hypoxic vasoconstriction by Y‐27632 in isolated intrapulmonary arteries and perfused lung of the rat , 2000, British journal of pharmacology.

[15]  B. Thompson,et al.  Polycythemia and vascular remodeling in chronic hypoxic pulmonary hypertension in guinea pigs. , 1991, Journal of applied physiology.

[16]  A. Shillington,et al.  Survival in Primary Pulmonary Hypertension: The Impact of Epoprostenol Therapy , 2002, Circulation.

[17]  H. White,et al.  Withdrawal of Statins Increases Event Rates in Patients With Acute Coronary Syndromes , 2002, Circulation.

[18]  S. Rich,et al.  Primary pulmonary hypertension: a vascular biology and translational research "Work in progress". , 2000, Circulation.

[19]  H. Mukundan,et al.  17Beta-estradiol decreases hypoxic induction of erythropoietin gene expression. , 2002, American journal of physiology. Regulatory, integrative and comparative physiology.

[20]  J. Liao,et al.  Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[21]  L. Ignarro,et al.  Negative modulation of nitric oxide synthase by nitric oxide and nitroso compounds. , 1995, Advances in pharmacology.

[22]  A. Vasudevan,et al.  Inhibiting geranylgeranylation blocks growth and promotes apoptosis in pulmonary vascular smooth muscle cells. , 1998, American journal of physiology. Lung cellular and molecular physiology.

[23]  花里 紀尚.  E4010, a selective phosphodiesterase 5 inhibitor, attenuates hypoxic pulmonary hypertension in rat , 1999 .

[24]  T. Dwyer,et al.  Calcium Mobilization and Muscle Contraction Induced by Acetylcholine in Swine Trachealis. , 1995, Journal of biomedical science.

[25]  J. Navarro-Antolín,et al.  Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. , 1998, The Journal of clinical investigation.

[26]  M. Moskowitz,et al.  Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. Bertoglio,et al.  Modulation of COX-2 Expression by Statins in Human Aortic Smooth Muscle Cells , 2001, The Journal of Biological Chemistry.

[28]  C. Dessy,et al.  Hydroxy-Methylglutaryl–Coenzyme A Reductase Inhibition Promotes Endothelial Nitric Oxide Synthase Activation Through a Decrease in Caveolin Abundance , 2001, Circulation.

[29]  P. Braquet,et al.  Effect of limonene and sobrerol on monocrotaline-induced lung alterations and pulmonary hypertension. , 1995, International archives of allergy and immunology.

[30]  W. Seeger,et al.  NO and reactive oxygen species are involved in biphasic hypoxic vasoconstriction of isolated rabbit lungs. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[31]  R. Johns,et al.  Soluble guanylate cyclase gene expression and localization in rat lung after exposure to hypoxia. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[32]  L. Edvinsson,et al.  Reduction of bFGF-induced smooth muscle cell proliferation and endothelin receptor mRNA expression by mevastatin and atorvastatin. , 2002, Biochemical pharmacology.

[33]  L. Reid,et al.  New findings in pulmonary arteries of rats with hypoxia-induced pulmonary hypertension. , 1976, British journal of experimental pathology.

[34]  Deepak L. Bhatt,et al.  Early and Sustained Survival Benefit Associated With Statin Therapy at the Time of Percutaneous Coronary Intervention , 2002, Circulation.

[35]  R. Johns,et al.  Effects of chronic hypoxia and altered hemodynamics on endothelial nitric oxide synthase expression in the adult rat lung. , 1998, The Journal of clinical investigation.

[36]  N. Voelkel,et al.  Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia. , 2001, Journal of applied physiology.

[37]  I. Shiojima,et al.  The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. , 2000, Nature Medicine.

[38]  J. Balligand,et al.  Hsp90 and Caveolin Are Key Targets for the Proangiogenic Nitric Oxide–Mediated Effects of Statins , 2001, Circulation research.

[39]  Y. Fukuchi,et al.  E-4010, a selective phosphodiesterase 5 inhibitor, attenuates hypoxic pulmonary hypertension in rats. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[40]  U. Laufs,et al.  Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. , 1998, Circulation.

[41]  M. Rabinovitch,et al.  Polycythemia and the acute hypoxic response in awake rats following chronic hypoxia. , 1983, Journal of applied physiology: respiratory, environmental and exercise physiology.

[42]  W. Jelkmann,et al.  Biology of erythropoietin. , 1994, The Clinical investigator.

[43]  D. Kornbrust,et al.  Animal safety and toxicology of simvastatin and related hydroxy-methylglutaryl-coenzyme A reductase inhibitors. , 1989, The American journal of medicine.

[44]  A. Mueck,et al.  Fluvastatin increases prostacyclin and decreases endothelin production by human umbilical vein endothelial cells. , 2000, International journal of clinical pharmacology and therapeutics.

[45]  A. Szczeklik,et al.  Antithrombotic actions of statins. , 2001, Medical science monitor : international medical journal of experimental and clinical research.

[46]  M. Humbert,et al.  Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. , 2001, The Journal of clinical investigation.

[47]  L. Dobrucki,et al.  Increased Nitric Oxide Bioavailability in Endothelial Cells Contributes to the Pleiotropic Effect of Cerivastatin , 2002, Circulation.

[48]  L. Chicoine,et al.  Maintained upregulation of pulmonary eNOS gene and protein expression during recovery from chronic hypoxia. , 1999, American journal of physiology. Heart and circulatory physiology.