Skip to main content
SpringerLink
Log in

The HMG-CoA reductase inhibitor, pravastatin, prevents the development of monocrotaline-induced pulmonary hypertension in the rat through reduction of endothelial cell apoptosis and overexpression of eNOS

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

HMG-CoA reductase inhibitors improve endothelial function and exert antiproliferative effects on vascular smooth muscle cells of systemic vessels. This study was aimed to assess the protective effects of pravastatin (an HMG-CoA reductase inhibitor) against monocrotaline-induced pulmonary hypertension in rats. Pravastatin (PS, 10 mg/kg/day) or vehicle were given orally for 28 days to Wistar male rats injected or not with monocrotaline (MC, 60 mg/kg intraperitonealy) and treated or not by Nω-nitro-L-arginine methyl ester (L-NAME) 15 mg/kg/day. At 4 weeks, monocrotaline-injected rats developed severe pulmonary hypertension, with an increase in right ventricular pressure (RVP) and right ventricle/left ventricle+septum weight ratio (RV/LV+S), associated with a decrease in pulmonary artery dilation induced either by acetylcholine or sodium nitroprusside. Hypertensive pulmonary arteries exhibited an increase in medial thickness, medial wall area, endothelial cell apoptosis, and a decrease of endothelial nitric oxide synthase (eNOS) expression. Monocrotaline-rat lungs showed a significant decrease of eNOS expression (4080±27 vs 12189±761 arbitrary density units [ADU] for MC and control groups respectively, P<0.01) and a significant increase of cleaved caspase-3 expression by western blotting (Control=11628±2395 vs MC=2326±2243 ADU, P<0.05). A non-significant trend toward a reduced mortality was observed with pravastatin (relative risk of death = 0.33; 95% confidence interval [0.08–1.30], P= 0.12 for MC+PS vs MC groups). Pravastatine induced a protection against the development of the pulmonary hypertension (RVP in mmHg: 30±3 vs 45±4 and RV/LV+S: 0.46±0.04 vs 0.62±0.05 for MC+PS and MC groups respectively, P<0.05) and was associated with a significant reduction of MC-induced thickening (61±6 μm vs 81±3 μm for MC+PS and MC groups respectively, P= 0.01) of the medial wall of the small intrapulmonary arteries. Pravastatin partially restored acetylcholine-induced pulmonary artery vasodilation in MC rats (Emax=65±5% and 46±3% for MC+PS and MC group respectively, P<0.05) but had no effect on acetylcholine-induced pulmonary artery vasodilation in MC+L-NAME rats. It also prevented apoptosis and restored eNOS expression of pulmonary artery endothelial cells, as well as in the whole lung. Pravastatin reduces the development of monocrotaline-induced pulmonary hypertension and improves endothelium-dependent pulmonary artery relaxation, probably through a reduced apoptosis and a restored eNOS expression of endothelial cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Asakage M, Tsuno NH, Kitayama J, Kawai K, Okaji Y, Yazawa K, Kaisaki S, Takahashi K, Nagawa H (2004) 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (pravastatin) inhibits endothelial cell proliferation dependent on G1 cell cycle arrest. Anticancer Drugs 15:625–632

    Article  PubMed  CAS  Google Scholar 

  • Bardou M, Goirand F, Marchand S, Rouget C, Devillier P, Dumas JP, Morcillo EJ, Rochette L, Dumas M (2001) Hypoxic vasoconstriction of rat main pulmonary artery: role of endogenous nitric oxide, potassium channels, and phosphodiesterase inhibition. J Cardiovasc Pharmacol 38:325–334

    Article  PubMed  CAS  Google Scholar 

  • Dhein S, Giessler C, Heinroth-Hoffmann I, Leineweber K, Seyfarth T, Brodde OE (2002) Changes in alpha(1)-adrenergic vascular reactivity in monocrotaline-treated rats. Naunyn–Schmiedeberg’s Arch Pharmacol 365:87–95

    Article  CAS  Google Scholar 

  • Dusi S, Donini M, Rossi F (1995) Mechanisms of NADPH oxidase activation in human neutrophils: p67phox is required for the translocation of rac 1 but not of rac 2 from cytosol to the membranes. Biochem J 308 ( Pt 3):991–994

    CAS  Google Scholar 

  • Galie N, Manes A, Farahani KV, Pelino F, Palazzini M, Negro L, Romanazzi S, Branzi A (2005) Pulmonary arterial hypertension associated to connective tissue diseases. Lupus 14:713–717

    Article  PubMed  CAS  Google Scholar 

  • Gerloff T, Schaefer M, Mwinyi J, Johne A, Sudhop T, Lutjohann D, Roots I, von Bergmann K (2006) Influence of the SLCO1B1*1b and *5 haplotypes on pravastatin’s cholesterol lowering capabilities and basal sterol serum levels. Naunyn–Schmiedeberg’s Arch Pharmacol 373:45–50

    Article  CAS  Google Scholar 

  • Girgis REm, Li D, Zhan X, Garcia JG, Tuder RM, Hassoun P, Johns RA (2003). Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Circ Physiol 285:H938–H945

    PubMed  CAS  Google Scholar 

  • Guignabert C, Raffestin B, Benferhat R, Raoul W, Zadigue P, Rideau D, Hamon M, Adnot S, Eddahibi S (2005) Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats. Circulation 111:2812–2819

    Article  PubMed  CAS  Google Scholar 

  • Guijarro C, Blanco-Colio LM, Massy ZA, O’Donnell MP, Kasiske BL, Keane, WF, Egido J (1999) Lipophilic statins induce apoptosis of human vascular smooth muscle cells. Kidney Int Suppl 71:S88–S91

    Article  PubMed  CAS  Google Scholar 

  • Hamelin BA, Turgeon J (1998) Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci 19:26–37

    Article  PubMed  CAS  Google Scholar 

  • Hatanaka T (2000) Clinical pharmacokinetics of pravastatin: mechanisms of pharmacokinetic events. Clin Pharmacokinet 39:397–412

    Article  PubMed  CAS  Google Scholar 

  • Hoeper MM (2005) Drug treatment of pulmonary arterial hypertension: current and future agents. Drugs 65:1337–1354

    Article  PubMed  CAS  Google Scholar 

  • Hongo M, Mawatari E, Sakai A Ruan Z, Koizumi T, Terasawa F, Yazaki Y, Kinoshita, O Ikeda U, Shibamoto T (2005) Effects of nicorandil on monocrotaline-induced pulmonary arterial hypertension in rats. J Cardiovasc Pharmacol 46: 452–458

    Article  PubMed  CAS  Google Scholar 

  • Honjo M, Tanihara H, Nishijima K, Kiryu J, Honda Y, Yue BY, Sawamura T (2002) Statin inhibits leukocyte-endothelial interaction and prevents neuronal death induced by ischemia-reperfusion injury in the rat retina. Arch Ophthalmol 120:1707–1713

    PubMed  CAS  Google Scholar 

  • Jain MK, Ridker PM (2005) Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov 4:977–987

    Article  PubMed  CAS  Google Scholar 

  • Jones PL, Rabinovitch M (1996) Tenascin-C is induced with progressive pulmonary vascular disease in rats and is functionally related to increased smooth muscle cell proliferation. Circ Res 79:1131–1142

    Google Scholar 

  • Joyce M, Kelly CJ, Chen G, Bouchier-Hayes DJ (2001) Pravastatin attenuates lower torso ischaemia-reperfusion-induced lung injury by upregulating constitutive endothelial nitric oxide synthase. Eur J Vasc Endovasc Surg 21:295–300

    Article  PubMed  CAS  Google Scholar 

  • Kaesemeyer WH, Caldwell RB, Huang J, Caldwell RW (1999) Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions. J Am Coll Cardiol 33:234–241

    Article  PubMed  CAS  Google Scholar 

  • Kaneta S, Satoh K, Kano S, Kanda M, Ichihara K (2003) All hydrophobic HMG-CoA reductase inhibitors induce apoptotic death in rat pulmonary vein endothelial cells. Atherosclerosis 170:237–243

    Article  PubMed  CAS  Google Scholar 

  • Kanno S, Wu YJ, Lee PC, Billiar TR, Ho C (2001) Angiotensin-converting enzyme inhibitor preserves p21 and endothelial nitric oxide synthase expression in monocrotaline-induced pulmonary arterial hypertension in rats. Circulation 104:945–950

    Article  PubMed  CAS  Google Scholar 

  • Kao PN (2005) Simvastatin treatment of pulmonary hypertension: an observational case series. Chest 127:1446–1452

    Article  PubMed  CAS  Google Scholar 

  • Kinlay S (2005) Potential vascular benefits of statins. Am J Med 118 Suppl 12A:62–67

    Article  PubMed  Google Scholar 

  • Koh KK (2000) Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability. Cardiovasc Res 47:648–657a

    Article  PubMed  CAS  Google Scholar 

  • Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, Sessa WC, Walsh K (2000) The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 6:1004–1010

    Article  PubMed  CAS  Google Scholar 

  • Laemmli UK, Beguin F, Gujer-Kellenberger G (1970) A factor preventing the major head protein of bacteriophage T4 from random aggregation. J Mol Biol 47:69–85

    Article  PubMed  CAS  Google Scholar 

  • Lam CF, Peterson TE, Croatt AJ, Nath KA, Katusic ZS (2005) Functional adaptation and remodeling of pulmonary artery in flow-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 289:H2334–H2341

    Article  PubMed  CAS  Google Scholar 

  • Laufs U, Liao JK (1998) Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 273:24266–24271

    Article  PubMed  CAS  Google Scholar 

  • Laufs U, Liao JK (2000) Direct vascular effects of HMG-CoA reductase inhibitors. Trends Cardiovasc Med 10:143–148

    Article  PubMed  CAS  Google Scholar 

  • Laufs U, Fata VL, Liao JK (1997) Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. J Biol Chem 272:31725–31729

    Article  PubMed  CAS  Google Scholar 

  • Laufs U, La Fata V, Plutzky J, Liao JK (1998) Upregulation of ndothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 97:1129–1135

    PubMed  CAS  Google Scholar 

  • Laufs U, Marra D, Node K, Liao JK (1999) 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27(Kip1). J Biol Chem 274:21926–21931

    Article  PubMed  CAS  Google Scholar 

  • Li X, Liu L, Tupper JC, Bannerman DD, Winn RK, Sebti SM, Hamilton AD, Harlan JM (2002) Inhibition of protein geranylgeranylation and RhoA/RhoA kinase pathway induces apoptosis in human endothelial cells. J Biol Chem 277:15309–15316

    Article  PubMed  CAS  Google Scholar 

  • Mason RP, Walter MF, Day CA, Jacob RF (2005) Intermolecular differences of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors contribute to distinct pharmacologic and pleiotropic actions. Am J Cardiol 96:11F–23F

    Article  PubMed  CAS  Google Scholar 

  • McLaughin VV, Hoeper MM (2005) Pulmonary arterial hypertension: the race for the most effective treatment. Am J Respir Crit Care Med 171:1199–1201

    Article  PubMed  Google Scholar 

  • Morita K, Ogawa Y, Tobise K (1996) Effect of endothelium of pulmonary artery vasoreactivity in monocrotaline-induced pulmonary hypertensive rats. Jpn Circ J 60:585–592

    Article  PubMed  CAS  Google Scholar 

  • Newton CJ, Ran G, Xie YX, Bilko D, Burgoyne CH, Adams I, Abidia A, McCollum PT, Atkin SL (2002) Statin-induced apoptosis of vascular endothelial cells is blocked by dexamethasone. J Endocrinol 174:7–16

    Article  PubMed  CAS  Google Scholar 

  • Nishimura T, Faul JL, Berry GJ, Vaszar LT, Qiu D, Pearl RG, Kao PN (2002) Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am J Respir Crit Care Med 166:1403–1408

    Article  PubMed  Google Scholar 

  • Nishimura T, Vaszar LT, Faul JL, Zhao G, Berry GJ, Shi L, Qiu D, Benson G, Pearl RG, Kao PN (2003) Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation 108:1640–1655

    Article  PubMed  CAS  Google Scholar 

  • Prie S, Stewart DJ, Dupuis J (1998) EndothelinA receptor blockade improves nitric oxide-mediated vasodilation in monocrotaline-induced pulmonary hypertension. Circulation 97:2169–2174

    PubMed  CAS  Google Scholar 

  • Pullamsetti S, Krick S, Yilmaz H, Ghofrani HA, Schudt C, Weissmann N, Fuchs B, Seeger W, Grimminger F, Schermuly RT (2005) Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration. Respir Res 6:128

    Article  PubMed  Google Scholar 

  • Rikitake Y, Liao JK (2005) Rho GTPases, statins, and nitric oxide. Circ Res 97:1232–1235

    Article  PubMed  CAS  Google Scholar 

  • Rinckel LA, Faris SL, Hitt ND, Kleinberg ME (1999) Rac1 disrupts p67phox/p40phox binding: a novel role for Rac in NADPH oxidase activation. Biochem Biophys Res Commun 263:118–122

    Article  PubMed  CAS  Google Scholar 

  • Rosenson RS (1999) Non-lipid-lowering effects of statins on atherosclerosis. Curr Cardiol Rep 1:225–232

    Article  PubMed  CAS  Google Scholar 

  • Runo JR, Loyd JE (2003) Primary pulmonary hypertension. Lancet 361:1533–1544

    Article  PubMed  Google Scholar 

  • Shah DI, Singh M (2006) Effect of bis(maltolato) oxovanadium on experimental vascular endothelial dysfunction. Naunyn–Schmiedeberg’s Arch Pharmacol 373:221–229

    Article  CAS  Google Scholar 

  • Sindermann JR, Fan L, Weigel KA, Troyer D, Muller JG, Schmidt A March KL, Breithardt G (2000) Differences in the effects of HMG-CoA reductase inhibitors on proliferation and viability of smooth muscle cells in culture. Atherosclerosis 150:331–341

    Article  PubMed  CAS  Google Scholar 

  • Takemoto M, Node K, Nakagami H, Liao Y, Grimm M, Takemoto Y, Kitakaze M, Liao JK (2001) Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest 108:1429–1437

    PubMed  CAS  Google Scholar 

  • Thomas HC, Lame MW, Dunston SK, Segall HJ, Wilson DW (1998) Monocrotaline pyrrole induces apoptosis in pulmonary artery endothelial cells. Toxicol Appl Pharmacol 151:236–244

    Article  PubMed  CAS  Google Scholar 

  • Tyler RC, Fagan KA, Unfer RC, Gorman C, McClarrion M, Bullock C, Rodman DM (1999) Vascular inflammation inhibits gene transfer to the pulmonary circulation in vivo. Am J Physiol 277:L1199–L1204

    PubMed  CAS  Google Scholar 

  • Wassmann S, Laufs U, Baumer AT, Muller K, Konkol C, Sauer H, Bohm M, Nickenig G (2001) Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol Pharmacol 59:646–654

    PubMed  CAS  Google Scholar 

  • Weitz-Schmidt G (2002) Statins as anti-inflammatory agents. Trends Pharmacol Sci 23:482–486

    Article  PubMed  CAS  Google Scholar 

  • Wright DG, Lefer DJ (2005) Statin mediated protection of the ischemic myocardium. Vascul Pharmacol 42:265–270

    Article  PubMed  CAS  Google Scholar 

  • Zhao YD, Courtman, DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ (2005) Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res 96:442–450

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the University of Burgundy.

Author information

Authors and Affiliations

  1. Laboratory of Experimental Cardiovascular Physiopathology and Pharmacology (EA2979), IFR 100 Faculty of Medicine, BP 87900, 21000, Dijon, France

    Pascal Guerard, Zo Rakotoniaina, Luc Rochette, Monique Dumas, Frederic Lirussi & Marc Bardou

  2. UMR 1154, INRA-Physiology, Faculty of Pharmacy, 5, rue Jean-Baptiste Clément, 92290, Châtenay-Malabry, France

    Françoise Goirand

  3. LPPCE Faculté de Médecine, 7, bd. Jeanne d’ Arc, BP 87900, 21079, Dijon, Cedex, France

    Pascal Guerard

Authors
  1. Pascal Guerard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zo Rakotoniaina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Françoise Goirand
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luc Rochette
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Monique Dumas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Frederic Lirussi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marc Bardou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pascal Guerard.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guerard, P., Rakotoniaina, Z., Goirand, F. et al. The HMG-CoA reductase inhibitor, pravastatin, prevents the development of monocrotaline-induced pulmonary hypertension in the rat through reduction of endothelial cell apoptosis and overexpression of eNOS. Naunyn-Schmied Arch Pharmacol 373, 401–414 (2006). https://doi.org/10.1007/s00210-006-0082-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-006-0082-1

Keywords

Search

Navigation