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Statins inhibit pulmonary artery smooth muscle cell proliferation by upregulation of HO-1 and p21WAF1

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Abstract

Simvastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, which has been shown to ameliorate the development of pulmonary hypertension in animal model by suppression of pulmonary artery smooth muscle cells (PASMCs) proliferation, yet its underlying molecular mechanisms are not completely understood. In this study, we show that simvastatin dose-dependently inhibited serotonin-stimulated PASMCs proliferation. This was accompanied with the parallel induction of heme oxyganase-1 (HO-1) and upregulation of p21WAF1. More importantly, we found that Tin-protoporphyrin (SnPP), a selective inhibitor of HO-1, could block the effect of simvastatin on inhibition of cell proliferation in response to serotonin and abolish simvastatin-induced p21WAF1 expression. The inhibitive effect of simvastatin on cell proliferation was also significantly suppressed by silencing p21WAF1 with siRNA transfection. The extent of effect of SnPP on inhibition of cell proliferation was similar to that of lack of p21WAF1 by siRNA transfection. Taken together, our study suggests that simvastatin inhibits PASMCs proliferation by sequential upregulation of HO-1 and p21WAF1 to benefit pulmonary hypertension.

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References

  • Ali OF, Growcott EJ, Butrous GS, Wharton J (2011) Pleiotropic effects of statins in distal human pulmonary artery smooth muscle cells. Respir Res 12:137

    Article  PubMed  CAS  Google Scholar 

  • Armitage J, Bowman L, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, Parish S, Peto R, Collins R (2010) Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 376:1658–1669

    Article  PubMed  Google Scholar 

  • Bruegel M, Teupser D, Haffner I, Mueller M, Thiery J (2006) Statins reduce macrophage inflammatory protein-1alpha expression in human activated monocytes. Clin Exp Pharmacol Physiol 33:1144–1149

    Article  PubMed  CAS  Google Scholar 

  • Chen L, Nakano K, Kimura S, Matoba T, Iwata E, Miyagawa M, Tsujimoto H, Nagaoka K, Kishimoto J, Sunagawa K, Egashira K (2011) Nanoparticle-mediated delivery of pitavastatin into lungs ameliorates the development and induces regression of monocrotaline-induced pulmonary artery hypertension. Hypertension 57:343–350

    Article  PubMed  CAS  Google Scholar 

  • Copaja M, Venegas D, Aranguiz P, Canales J, Vivar R, Catalan M, Olmedo I, Rodriguez AE, Chiong M, Leyton L, Lavandero S, Diaz-Araya G (2011) Simvastatin induces apoptosis by a Rho-dependent mechanism in cultured cardiac fibroblasts and myofibroblasts. Toxicol Appl Pharmacol 255:57–64

    Article  PubMed  CAS  Google Scholar 

  • Danesh FR, Sadeghi MM, Amro N, Philips C, Zeng L, Lin S, Sahai A, Kanwar YS (2002) 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/p21 signaling pathway: implications for diabetic nephropathy. Proc Natl Acad Sci U S A 99:8301–8305

    Article  PubMed  CAS  Google Scholar 

  • Deanfield JE, Sellier P, Thaulow E, Bultas J, Yunis C, Shi H, Buch J, Beckerman B (2010) Potent anti-ischaemic effects of statins in chronic stable angina: incremental benefit beyond lipid lowering? Eur Heart J 31:2650–2659

    Article  PubMed  CAS  Google Scholar 

  • Girgis RE, Mozammel S, Champion HC, Li D, Peng X, Shimoda L, Tuder RM, Johns RA, Hassoun PM (2007) Regression of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Lung Cell Mol Physiol 292:L1105–L1110

    Article  PubMed  CAS  Google Scholar 

  • Golovina VA, Blaustein MP (2006) Preparation of primary cultured mesenteric artery smooth muscle cells for fluorescent imaging and physiological studies. Nat Protoc 1:2681–2687

    Article  PubMed  CAS  Google Scholar 

  • Guerard P, Rakotoniaina Z, Goirand F, Rochette L, Dumas M, Lirussi F, Bardou M (2006) 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 Schmiedebergs Arch Pharmacol 373:401–414

    Article  PubMed  CAS  Google Scholar 

  • Hansmann G, de Jesus Perez VA, Alastalo TP, Alvira CM, Guignabert C, Bekker JM, Schellong S, Urashima T, Wang L, Morrell NW, Rabinovitch M (2008) An antiproliferative BMP-2/PPARgamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension. J Clin Invest 118:1846–1857

    Article  PubMed  CAS  Google Scholar 

  • Hinkelmann U, Grosser N, Erdmann K, Schroder H, Immenschuh S (2010) Simvastatin-dependent up-regulation of heme oxygenase-1 via mRNA stabilization in human endothelial cells. Eur J Pharm Sci 41:118–124

    Article  PubMed  CAS  Google Scholar 

  • Hsu HH, Ko WJ, Hsu JY, Chen JS, Lee YC, Lai IR, Chen CF (2009) Simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats. Respir Res 10:32

    Article  PubMed  Google Scholar 

  • Ikeda T, Nakamura K, Akagi S, Kusano KF, Matsubara H, Fujio H, Ogawa A, Miura A, Miura D, Oto T, Yamanaka R, Otsuka F, Date H, Ohe T, Ito H (2010) Inhibitory effects of simvastatin on platelet-derived growth factor signaling in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. J Cardiovasc Pharmacol 55:39–48

    Article  PubMed  CAS  Google Scholar 

  • Kikuchi G, Yoshida T, Noguchi M (2005) Heme oxygenase and heme degradation. Biochem Biophys Res Commun 338:558–567

    Article  PubMed  CAS  Google Scholar 

  • Kumar D, Bhaskaran M, Alagappan L, Tori D, Yadav I, Konkimalla S, Magoon S, Singhal PC (2010) Heme oxygenase-1 modulates mesangial cell proliferation by p21 Waf1 upregulation. Ren Fail 32:254–258

    Article  PubMed  CAS  Google Scholar 

  • Lee TS, Chang CC, Zhu Y, Shyy JY (2004) Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection. Circulation 110:1296–1302

    Article  PubMed  CAS  Google Scholar 

  • Leffler CW, Parfenova H, Jaggar JH (2011) Carbon monoxide as an endogenous vascular modulator. Am J Physiol Heart Circ Physiol 301:H1–H11

    Article  PubMed  CAS  Google Scholar 

  • Li M, Liu Y, Dutt P, Fanburg BL, Toksoz D (2007) Inhibition of serotonin-induced mitogenesis, migration, and ERK MAPK nuclear translocation in vascular smooth muscle cells by atorvastatin. Am J Physiol Lung Cell Mol Physiol 293:L463–L471

    Article  PubMed  CAS  Google Scholar 

  • Li M, Sun X, Li Z, Liu Y (2009) Inhibition of cGMP phosphodiesterase 5 suppresses serotonin signalling in pulmonary artery smooth muscles cells. Pharmacol Res 59:312–318

    Article  PubMed  CAS  Google Scholar 

  • Li M, Li Z, Sun X, Yang L, Fang P, Liu Y, Li W, Xu J, Lu J, Xie M, Zhang D (2010) Heme oxygenase-1/p21WAF1 mediates peroxisome proliferator-activated receptor-gamma signaling inhibition of proliferation of rat pulmonary artery smooth muscle cells. FEBS J 277:1543–1550

    Article  PubMed  CAS  Google Scholar 

  • Liang OD, Mitsialis SA, Chang MS, Vergadi E, Lee C, Aslam M, Fernandez-Gonzalez A, Liu X, Baveja R, Kourembanas S (2011) Mesenchymal stromal cells expressing heme oxygenase-1 reverse pulmonary hypertension. Stem Cells 29:99–107

    Article  PubMed  CAS  Google Scholar 

  • Maclean MR, Dempsie Y (2010) The serotonin hypothesis of pulmonary hypertension revisited. Adv Exp Med Biol 661:309–322

    Article  PubMed  CAS  Google Scholar 

  • Morita T (2005) Heme oxygenase and atherosclerosis. Arterioscler Thromb Vasc Biol 25:1786–1795

    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 108:1640–1645

    Article  PubMed  CAS  Google Scholar 

  • Paraskevas KI, Athyros VG, Briana DD, Kakafika AI, Karagiannis A, Mikhailidis DP (2007) Statins exert multiple beneficial effects on patients undergoing percutaneous revascularization procedures. Curr Drug Targets 8:942–951

    Article  PubMed  CAS  Google Scholar 

  • Peinado VI, Pizarro S, Barbera JA (2008) Pulmonary vascular involvement in COPD. Chest 134:808–814

    Article  PubMed  CAS  Google Scholar 

  • Raval CM, Lee PJ (2010) Heme oxygenase-1 in lung disease. Curr Drug Targets 11:1532–1540

    PubMed  CAS  Google Scholar 

  • Roos TU, Heiss EH, Schwaiberger AV, Schachner D, Sroka IM, Oberan T, Vollmar AM, Dirsch VM (2011) Caffeic acid phenethyl ester inhibits PDGF-induced proliferation of vascular smooth muscle cells via activation of p38 MAPK, HIF-1alpha, and heme oxygenase-1. J Nat Prod 74:352–356

    Article  PubMed  CAS  Google Scholar 

  • Rothman RB, Cadet JL, Dersch CM, McCoy MT, Lehrmann E, Becker KG, Bader M, Alenina N, Baumann MH (2011) Altered gene expression in pulmonary tissue of tryptophan hydroxylase-1 knockout mice: implications for pulmonary arterial hypertension. PLoS One 6:e17735

    Article  PubMed  CAS  Google Scholar 

  • Schwer CI, Guerrero AM, Humar M, Roesslein M, Goebel U, Stoll P, Geiger KK, Pannen BH, Hoetzel A, Schmidt R (2008) Heme oxygenase-1 inhibits the proliferation of pancreatic stellate cells by repression of the extracellular signal-regulated kinase1/2 pathway. J Pharmacol Exp Ther 327:863–871

    Article  PubMed  CAS  Google Scholar 

  • Seidel P, Goulet S, Hostettler K, Tamm M, Roth M (2010) DMF inhibits PDGF-BB induced airway smooth muscle cell proliferation through induction of heme-oxygenase-1. Respir Res 11:145

    Article  PubMed  Google Scholar 

  • Sitbon O, Galie N (2010) Treat-to-target strategies in pulmonary arterial hypertension: the importance of using multiple goals. Eur Respir Rev 19:272–278

    Article  PubMed  CAS  Google Scholar 

  • Sitbon O, Simonneau G (2011) Optimal management of severe pulmonary arterial hypertension. Eur Respir Rev 20:254–261

    Article  PubMed  CAS  Google Scholar 

  • Spampanato C, De Maria S, Sarnataro M, Giordano E, Zanfardino M, Baiano S, Carteni M, Morelli F (2012) Simvastatin inhibits cancer cell growth by inducing apoptosis correlated to activation of Bax and down-regulation of BCL-2 gene expression. Int J Oncol 40:935–941

    PubMed  CAS  Google Scholar 

  • Toth PP (2010) Drug treatment of hyperlipidaemia: a guide to the rational use of lipid-lowering drugs. Drugs 70:1363–1379

    Article  PubMed  CAS  Google Scholar 

  • Tu YP, Chuang SJ, Chen SC, Liu YH, Chen CF, Hour TC (2011) Simvastatin induces the expression of hemeoxygenase-1 against ischemia-reperfusion injury on the testes in rats. Toxicol Lett 24:24

    Google Scholar 

  • Wu ML, Ho YC, Lin CY, Yet SF (2011) Heme oxygenase-1 in inflammation and cardiovascular disease. Am J Cardiovasc Dis 1:150–158

    PubMed  CAS  Google Scholar 

  • Yang X, Long L, Reynolds PN, Morrell NW (2011) Expression of mutant BMPR-II in pulmonary endothelial cells promotes apoptosis and a release of factors that stimulate proliferation of pulmonary arterial smooth muscle cells. Pulm Circ 1:103–110

    PubMed  CAS  Google Scholar 

  • Zhang WH, Zhang YJ, Liu CP, Yu BX, Lu WX (2011) Simvastatin protects against the development of monocrotaline-induced pulmonary hypertension in rats via a heme oxygenase-1-dependent pathway. Exp Lung Res 37:492–499

    Article  PubMed  CAS  Google Scholar 

  • Zhou H, Liu H, Porvasnik SL, Terada N, Agarwal A, Cheng Y, Visner GA (2006) Heme oxygenase-1 mediates the protective effects of rapamycin in monocrotaline-induced pulmonary hypertension. Lab Investig 86:62–71

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by Chinese National Science Foundation (81070045) and the start-up package to Manxiang Li from the First Affiliated Hospital of Medical College of Xi’an Jiaotong University, P.R. China.

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Authors and Affiliations

  1. Respiratory Diseases Research Center, The Second Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, Shaanxi, 710004, People’s Republic of China

    Manxiang Li, Yuan Liu, Hongyang Shi, Yonghong Zhang, Guizuo Wang, Jing Xu, Jiamei Lu, Dexin Zhang, Xinming Xie, Dong Han, Yuanyuan Wu & Shaojun Li

  2. Respiratory Diseases Research Center, The Second Affiliated Hospital of Medical College, Xi’an Jiaotong University, No. 157 West 5th Road, Xi’an, Shaanxi, 710004, People’s Republic of China

    Manxiang Li

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  1. Manxiang Li
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Correspondence to Manxiang Li.

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Li, M., Liu, Y., Shi, H. et al. Statins inhibit pulmonary artery smooth muscle cell proliferation by upregulation of HO-1 and p21WAF1 . Naunyn-Schmiedeberg's Arch Pharmacol 385, 961–968 (2012). https://doi.org/10.1007/s00210-012-0768-5

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  • DOI: https://doi.org/10.1007/s00210-012-0768-5

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