Protective Effects of Simvastatin on Monocrotaline-Induced Pulmonary Arteral Hypertension in Rats_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

DINGYongjie ¹ , ZHANGBenyan ² ,  LIMin ¹

1. Department of Respiratory Medicine, Shanghai Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R.China;
2. Department of Pathology, Shanghai Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R.China;

Corresponding?author：

LIMin, Email: limin_4212@163.com

Keywords：

Pulmonary arterial hypertension; Simvastatin; Monocrotaline; Vascular remodeling; Prevention

DOI：

10.7507/1671-6205.201606049

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Objective To observe the protective effects of simvastatin at different stages on monocrotaline (MCT) induced pulmonary arteral hypertension (PAH) in rats and evaluate the early preventive effect of simvastatin. Methods Twenty-four male SD rats were randomized into a control group, a PAH group, an early intervention group, and a late intervention group, with 6 rats in each group. The rats in the control group received intraperitoneal injection of normal saline (NS) on d₀. The rats in the PAH group received one-off intraperitoneal injection of MCT (50 mg/kg) on d₀. The rats in the early intervention group were pretreated with oral gavage of simvastatin (20 mg·kg^–1·d^–1)(d_–7––1) before the intraperitoneal one-off injection of MCT (50 mg/kg, d₀) and continued with oral gavage of simvastatin for 14 days (d_1~14). The rats in the late intervention group received one-off intraperitoneal injection of MCT (50 mg/kg)(d₀) and oral gavage of simvastatin (20 mg·kg^–1·d^–1) for the next 21 days (d_15~35). Thirty-five days after the MCT injection (d₃₆), mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) were measured by right heart catheter. Then the rats were sacrificed for separating the heart and lung, the right ventricular hypertrophy index (RVHI) and percentage of small pulmonary arteries media thickness (WT%), the inflammation score around the small pulmonary arterial were recorded. Results Compared with those in the PAH group, RVSP, mPAP, RVHI and WT% in two simvastatin interventiongroups got much better (P＜0.01), and the inflammation score around the small pulmonary arterial declined (P＜0.05). Compared with those in the late intervention group, RVSP, mPAP in the early intervention group improved (P＜0.05) and WT% decreased more significantly (P＜0.01). However RVHI and the inflammation score around the small pulmonary arterial were not different between two simvastatin intervention groups. Conclusions Both early intervention and late intervention with simvastatin can reduce RVSP, mPAP and WT% in MCT induced PAH rats. Compared with later intervention, early intervention can prevent PAH more remarkably.

Citation： DINGYongjie, ZHANGBenyan, LIMin. Protective Effects of Simvastatin on Monocrotaline-Induced Pulmonary Arteral Hypertension in Rats. Chinese Journal of Respiratory and Critical Care Medicine, 2017, 16(1): 64-70. doi: 10.7507/1671-6205.201606049 Copy

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2.	D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med, 1991, 115(5): 343-349.
3.	Ryerson CJ, Nayar S, Swiston JR, et al. Pharmacotherapy in pulmonary arterial hypertension: a systematic review and meta-analysis. Respir Res, 2010, 11(1): 12.
4.	Bogaard HJ, Abe K, Vonk Noordegraaf A, et al. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest, 2009, 135(3): 794-804.
5.	Rai PR, Cool CD, King JA, et al. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med, 2008, 178(6): 558-564.
6.	Humbert M, Hoeper MM. Severe pulmonary arterial hypertension: a forme fruste of cancer? Am J Respir Crit Care Med, 2008, 178(6): 551-552.
7.	Chan SY, Loscalzo J. Pathogenic mechanisms of pulmonary arterial hypertension. J Mol Cell Cardiol, 2008, 44(1): 14-30.
8.	Kao PN. Simvastatin treatment of pulmonary hypertension: an observational case series. Chest, 2005, 127(4): 1446-1452.
9.	Wilkins MR, Ali O, Bradlow W, et al. Simvastatin as a treatment for pulmonary hypertension trial. Am J Respir Crit Care Med, 2010, 181(10): 1106-1113.
10.	Zhao L, Sebkhi A, Ali O, et al. Simvastatin and sildenafil combine to attenuate pulmonary hypertension. Eur Respir J, 2009, 34(4): 948-957.
11.	杜軍保, 唐朝樞. 肺動脈高壓. 北京: 北京大學醫學出版社, 2010, 252-261.
12.	Lee SD, Shroyer KR, Markham NE, et al. Monoclonal endothelial cell proliferation in present in primary but not second pulmonary hypertension. J Clin Invest, 1998, 101(5):927-934.
13.	Stenmark KR, Meyrick B, Galie N, et al. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol, 2009, 297(6): 1013-1032.
14.	Jasmin JF, Lucas M, Cernacek P, et al. Effectiveness of a nonselective ETA/B and a selective ETA antagonist in rats with monocrotaline-induced pulmonary hypertension. Circulation, 2001, 103(2): 314-318.
15.	Ghodsi F, Will JA. Changes in pulmonary structure and function induced by monocrotaline intoxication. Am J Physiol, 1981, 240(2): 149-155.
16.	Lappin PB, Ross KL, King LE, et al. The response of pulmonary vascular endothelial cells to monocrotaline pyrrole: cell proliferation and DNA synthesis in vitro and in vivo. Toxicol Appl Pharmacol, 1998, 150(1): 37-48.
17.	Toya SP, Malik AB. Role of endothelial injury in disease mechanisms and contribution of progenitorcells in mediating endothelial repair. Immunobiology, 2012, 217(5): 569-580.
18.	Lee JH, Lee DS, Kim EK, et al. Simvastatin inhibits cigarette smoking-induced emphysema and pulmonary hypertension in rat lungs. Am J Respir Crit Care Med, 2005, 172(8):987-993.
19.	Ii M, Losordo DW. Statins and the endothelium. Vascul Pharmacol, 2007, 46(1): 1-9.
20.	Nishimura T, Faul JL, Berry GJ, et al. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am J Respir Crit Care Med, 2002, 166(10):1403-1408.
21.	Balakumar P, Kathuria S, Taneja G, et al. Is targeting eNOS a key mechanistic insight of cardiovascular defensive potentials of statins? J Mol Cell Cardiol, 2012, 52(1): 83-92.
22.	Kureishi Y, Luo Z, Shiojima I, et al. The HMG-CoA reductase inhibitor simvastatin activates the proteinkinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med, 2000, 6(9): 1004-1010.
23.	Plenz GA, Hofnagel O, Robenek H. Differential modulation of caveolin-1 expression in cells of the vasculature by statins. Circulation, 2004, 109(2): e7-e8.
24.	Degraeve F, Bolla M, Blaie S, et al. Modulation of COX-2 expression by statins in human aortic smooth muscle cells. Involvement of geranylgeranylated proteins. J Biol Chem, 2001, 276(50): 46849-46855.
25.	Hernández-Perera O, Pérez-Sala D, Navarro-Antolin J, 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. J Clin Invest, 1998, 101(12):2711-2719.
26.	Mraiche F, Cena J, Das D, et al. Effects of statins on vascular function of endothelin-1. Br J Pharmacol, 2005, 144(5):715-726.
27.	Wilson SH, Hermann J, Lerman LO, et al. Simvastatin preserves the structure of coronary adventitiaI vasa vasorum in experimental hypercholsterolemia independent of lipid 1owering. Circulation, 2002, 105(4):415-418.
28.	Schafer M, Schafer C , Ewald N, et al. Role of redox signaling in the autonomous proliferative response of endothelial cells to hypoxia. Circ Res, 2003, 92(9):1010-1015.
29.	Schaefer CA1, Kuhlmann CR, Weiterer S, et al. Statins inhibit hypoxia-induced endothelial proliferation by preventing calcium-induced ROS formation. Atherosclerosis, 2006, 185(2):290-296.
30.	Kaneta S, Satoh K, Kano S, et al. All hydrophobic HMG-CoA reductase inhibitors induce apoptotic death in rat pulmonary vein endothelial cells. Atherosclerosis. 2003, 170(2):237-243.
31.	Vincent L, Chen W, Hong L, et al. Inhibition of endothelial cell migration by cerivastatin, an HMG-CoA reductase inhibitor: contribution to its anti-angiogenic effect. FEBS Lett, 2001, 495(3):159-166.
32.	Laufs U, Marra D, Node K, et al. 3-Hydroxy-3-methyl-glutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27(Kip1). J Biol Chem, 1999, 274(31):21926-21931.
33.	Sindermann JR, Fan L, Weigle KA, et al. Differences in the effects of the HMG- CoA reductase inhibitors on proliferation and viability of smooth muscIe cells in culture. Atherosclerosis, 2000, 150(2):331-341.
34.	Li M, Liu Y, Dutt P, et al. 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, 2007, 293(2): 463-471.
35.	Nishimura T, Vaszar LT, Faul JL, et al. Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation, 2003, 108(13):1640-1645.
36.	Cheng G, Shan J, Xu G, et al. Apoptosis induced by simvastatin in rat vascular smooth muscle cell through Ca²⁺-calpain and caspase-3 dependent pathway. Pharmacol Res, 2003, 48(6):571-578.
37.	陸慰萱, 王辰. 肺循環病學. 北京:人民衛生出版社, 2007, 89-103.
38.	Hauck L, Harms C, Grothe D, et al. Critical role for FoxO3a-dependent regulation of p21CIP1/WAF1 in response to statin signaling in cardiac myocytes. Circ Res, 2007, 100(1): 50-60.

1. ?McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension. Circulation, 2009, 119(16): 2250-2294.
2. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med, 1991, 115(5): 343-349.
3. Ryerson CJ, Nayar S, Swiston JR, et al. Pharmacotherapy in pulmonary arterial hypertension: a systematic review and meta-analysis. Respir Res, 2010, 11(1): 12.
4. Bogaard HJ, Abe K, Vonk Noordegraaf A, et al. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest, 2009, 135(3): 794-804.
5. Rai PR, Cool CD, King JA, et al. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med, 2008, 178(6): 558-564.
6. Humbert M, Hoeper MM. Severe pulmonary arterial hypertension: a forme fruste of cancer? Am J Respir Crit Care Med, 2008, 178(6): 551-552.
7. Chan SY, Loscalzo J. Pathogenic mechanisms of pulmonary arterial hypertension. J Mol Cell Cardiol, 2008, 44(1): 14-30.
8. Kao PN. Simvastatin treatment of pulmonary hypertension: an observational case series. Chest, 2005, 127(4): 1446-1452.
9. Wilkins MR, Ali O, Bradlow W, et al. Simvastatin as a treatment for pulmonary hypertension trial. Am J Respir Crit Care Med, 2010, 181(10): 1106-1113.
10. Zhao L, Sebkhi A, Ali O, et al. Simvastatin and sildenafil combine to attenuate pulmonary hypertension. Eur Respir J, 2009, 34(4): 948-957.
11. 杜軍保, 唐朝樞. 肺動脈高壓. 北京: 北京大學醫學出版社, 2010, 252-261.
12. Lee SD, Shroyer KR, Markham NE, et al. Monoclonal endothelial cell proliferation in present in primary but not second pulmonary hypertension. J Clin Invest, 1998, 101(5):927-934.
13. Stenmark KR, Meyrick B, Galie N, et al. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol, 2009, 297(6): 1013-1032.
14. Jasmin JF, Lucas M, Cernacek P, et al. Effectiveness of a nonselective ETA/B and a selective ETA antagonist in rats with monocrotaline-induced pulmonary hypertension. Circulation, 2001, 103(2): 314-318.
15. Ghodsi F, Will JA. Changes in pulmonary structure and function induced by monocrotaline intoxication. Am J Physiol, 1981, 240(2): 149-155.
16. Lappin PB, Ross KL, King LE, et al. The response of pulmonary vascular endothelial cells to monocrotaline pyrrole: cell proliferation and DNA synthesis in vitro and in vivo. Toxicol Appl Pharmacol, 1998, 150(1): 37-48.
17. Toya SP, Malik AB. Role of endothelial injury in disease mechanisms and contribution of progenitorcells in mediating endothelial repair. Immunobiology, 2012, 217(5): 569-580.
18. Lee JH, Lee DS, Kim EK, et al. Simvastatin inhibits cigarette smoking-induced emphysema and pulmonary hypertension in rat lungs. Am J Respir Crit Care Med, 2005, 172(8):987-993.
19. Ii M, Losordo DW. Statins and the endothelium. Vascul Pharmacol, 2007, 46(1): 1-9.
20. Nishimura T, Faul JL, Berry GJ, et al. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am J Respir Crit Care Med, 2002, 166(10):1403-1408.
21. Balakumar P, Kathuria S, Taneja G, et al. Is targeting eNOS a key mechanistic insight of cardiovascular defensive potentials of statins? J Mol Cell Cardiol, 2012, 52(1): 83-92.
22. Kureishi Y, Luo Z, Shiojima I, et al. The HMG-CoA reductase inhibitor simvastatin activates the proteinkinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med, 2000, 6(9): 1004-1010.
23. Plenz GA, Hofnagel O, Robenek H. Differential modulation of caveolin-1 expression in cells of the vasculature by statins. Circulation, 2004, 109(2): e7-e8.
24. Degraeve F, Bolla M, Blaie S, et al. Modulation of COX-2 expression by statins in human aortic smooth muscle cells. Involvement of geranylgeranylated proteins. J Biol Chem, 2001, 276(50): 46849-46855.
25. Hernández-Perera O, Pérez-Sala D, Navarro-Antolin J, 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. J Clin Invest, 1998, 101(12):2711-2719.
26. Mraiche F, Cena J, Das D, et al. Effects of statins on vascular function of endothelin-1. Br J Pharmacol, 2005, 144(5):715-726.
27. Wilson SH, Hermann J, Lerman LO, et al. Simvastatin preserves the structure of coronary adventitiaI vasa vasorum in experimental hypercholsterolemia independent of lipid 1owering. Circulation, 2002, 105(4):415-418.
28. Schafer M, Schafer C , Ewald N, et al. Role of redox signaling in the autonomous proliferative response of endothelial cells to hypoxia. Circ Res, 2003, 92(9):1010-1015.
29. Schaefer CA1, Kuhlmann CR, Weiterer S, et al. Statins inhibit hypoxia-induced endothelial proliferation by preventing calcium-induced ROS formation. Atherosclerosis, 2006, 185(2):290-296.
30. Kaneta S, Satoh K, Kano S, et al. All hydrophobic HMG-CoA reductase inhibitors induce apoptotic death in rat pulmonary vein endothelial cells. Atherosclerosis. 2003, 170(2):237-243.
31. Vincent L, Chen W, Hong L, et al. Inhibition of endothelial cell migration by cerivastatin, an HMG-CoA reductase inhibitor: contribution to its anti-angiogenic effect. FEBS Lett, 2001, 495(3):159-166.
32. Laufs U, Marra D, Node K, et al. 3-Hydroxy-3-methyl-glutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27(Kip1). J Biol Chem, 1999, 274(31):21926-21931.
33. Sindermann JR, Fan L, Weigle KA, et al. Differences in the effects of the HMG- CoA reductase inhibitors on proliferation and viability of smooth muscIe cells in culture. Atherosclerosis, 2000, 150(2):331-341.
34. Li M, Liu Y, Dutt P, et al. 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, 2007, 293(2): 463-471.
35. Nishimura T, Vaszar LT, Faul JL, et al. Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation, 2003, 108(13):1640-1645.
36. Cheng G, Shan J, Xu G, et al. Apoptosis induced by simvastatin in rat vascular smooth muscle cell through Ca²⁺-calpain and caspase-3 dependent pathway. Pharmacol Res, 2003, 48(6):571-578.
37. 陸慰萱, 王辰. 肺循環病學. 北京:人民衛生出版社, 2007, 89-103.
38. Hauck L, Harms C, Grothe D, et al. Critical role for FoxO3a-dependent regulation of p21CIP1/WAF1 in response to statin signaling in cardiac myocytes. Circ Res, 2007, 100(1): 50-60.

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