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マウス左室圧負荷モデルの左右心室筋に対してphosphodiesterase 5阻害薬sildenafilが及ぼす影響の検討

今井, 洋介 東京大学 DOI:10.15083/0002003283

2022.03.09

概要

【背景と目的】
左心不全に引き続き右心機能が低下すると、臨床予後が悪化することが近年報告され、左心病態下における右心機能の重要性が注目されている。しかし心室間相互作用は構造的な関係からの検討が主体であり、右室心筋に生じる分子的な影響の解析はこれまでほとんど行われてこなかった。また右室リモデリングの研究は専ら不全状態の右室を対象に行われており、肺高血圧を伴わない右室におけるリモデリングはほとんど検討されていない。そこで本研究では、左心不全を生じうる左心病変の1つである左室肥大を対象とし、左室肥大を生じうる圧負荷が短期間で右室に生じる分子リモデリングについて動物モデルを用いて検討した(目的1)。一方、心不全治療薬の研究では細胞内cyclic GMP(cGMP)シグナルを増強する薬剤が近年注目されている。その中でもphosphodiesterase5(PDE5)阻害薬sildenafilは肺動脈平滑筋拡張作用を有することから肺高血圧治療に用いられているが、心機能への影響、左室リモデリングの抑制および改善効果、心不全患者への効果について最も研究されてきた薬剤の1つである。しかしsildenafilの右心臓に対する作用については肺動脈狭窄等による右室後負荷増大モデル等で検討されているのみであり、分子生物学的な検討も行われてこなかった。本研究ではsildenafilの心不全治療薬としての新たな作用を検索するため、sildenafilが左心病変早期の右室へ及ぼす影響に関して横行大動脈縮窄(transverse aortic constriction:TAC)マウスを用いて調査を行った(目的2)。

【方法と結果】
実験にはオスのC57BL/6Jマウスを用いた。27ゲージの太さのTACによって左室後負荷を増加させた。Sham手術を受けたコントロール群、TAC手術を受けsildenafil投薬を受けない群、TAC手術を受けsildenafil(200mg/kg/day)投薬を受ける群の3グループを設定し、TAC手術2日後に心エコー検査、カテーテル検査による生理学的評価、および摘出した心臓組織でのタンパク、RNA解析を含む分子生物学な検討を行った。カテーテル検査では大動脈縮窄による左室後負荷の増大を認め(139mmHg vs 89mmHg、p=0.004)たが、平均右室圧は上昇していなかった(16mmHg vs 13mmHg、p=0.30)。2日間のTACによって心臓重量は増加した(+13%、p=0.002)が、右室重量や両心の収縮機能は保たれていた。興味深いことに、左室心筋のみならず右室自由壁においても、brain natriuretic peptide(BNP)およびregulator of calcineurin1(RCAN1)のmRNA発現やextracellular signal–regulated kinases1/2(ERK1/2)のリン酸化が亢進しており、分子リモデリングプロセスが既に存在していることが認められた。Sildenafil投与は左室のみならず右室においてもBNP・RCAN1のmRNA発現増加を軽減した。Sildenafilがリモデリング抑制シグナルへ与える影響については、cGMPシグナルの主要なエフェクターキナーゼであるcGMP-dependent protein kinase-1α(PKG-1α)、および病的リモデリング形成に中心的役割を果たすGαq-coupled signalingに注目し、その不活性化因子であるregulator of G protein signaling2(RGS2)、およびRGS4の細胞内における局在変化をwestern blotにて検討した。TAC後の左右心室心筋においてsildenafilはPKG-1αの細胞質から細胞膜への移動を誘導した。左右心室心筋におけるRGS2・RGS4の細胞内局在へのsildenafilの影響は検出できなかった。これらの結果より、sildenafilにより活性化されたPKG-1αが右心室における分子リモデリング抑制に寄与するものと考えられた。

【結語】
左心病変早期には二次性肺高血圧が生じておらずとも右室に分子リモデリングを認めた。PDE5阻害薬sildenafilは左心病変早期の右室にて分子リモデリングを抑制し、その機序にはPKG-1αの活性化が関与することが示唆された。

参考文献

1. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Rønnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A; ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 33: 1787-1847, 2012.

2. Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling--concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol 35: 569-582, 2000.

3. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart 93: 1137-1146, 2007.

4. 厚生労働省大臣官房統計情報部. 平成 26 年 患者調査(傷病分類編). (オンライン) (引用日: 2016 年 2 月 12 日.) http://www.mhlw.go.jp/toukei/saikin/hw/kanja/10syoubyo/dl/h26syobyo.pdf.

5. Tsuchihashi-Makaya M, Hamaguchi S, Kinugawa S, Yokota T, Goto D, Yokoshiki H, Kato N, Takeshita A, Tsutsui H; JCARE-CARD Investigators. Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). Circ J 73: 1893-1900, 2009.

6. Shiba N, Watanabe J, Shinozaki T, Koseki Y, Sakuma M, Kagaya Y, Shirato K; CHART Investigators. Analysis of chronic heart failure registry in the Tohoku district: third year follow-up. Circ J 68: 427-434, 2004.

7. Zakeri R, Mohammed SF. Epidemiology of right ventricular dysfunction in heart failure with preserved ejection fraction. Curr Heart Fail Rep 12: 295-301, 2015.

8. Shah AM, Shah SJ, Anand IS, Sweitzer NK, O'Meara E, Heitner JF, Sopko G, Li G, Assmann SF, McKinlay SM, Pitt B, Pfeffer MA, Solomon SD. Cardiac structure and function in heart failure with preserved ejection fraction: baseline findings from the echocardiographic study of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial. Circ Heart Fail 7: 104-115, 2014.

9. Morris DA, Gailani M, Vaz Pérez A, Blaschke F, Dietz R, Haverkamp W, Özcelik C. Right ventricular myocardial systolic and diastolic dysfunction in heart failure with normal left ventricular ejection fraction. J Am Soc Echocardiogr 24: 886-897, 2011.

10. Guazzi M, Bandera F, Pelissero G, Castelvecchio S, Menicanti L, Ghio S, Temporelli PL, Arena R. Tricuspid annular plane systolic excursion and pulmonary arterial systolic pressure relationship in heart failure: an index of right ventricular contractile function and prognosis. Am J Physiol Heart Circ Physiol 305: H1373-H1381, 2013.

11. Puwanant S, Priester TC, Mookadam F, Bruce CJ, Redfield MM, Chandrasekaran K. Right ventricular function in patients with preserved and reduced ejection fraction heart failure. Eur J Echocardiogr 10: 733-737, 2009.

12. Mohammed SF, Hussain I, AbouEzzeddine OF, Takahama H, Kwon SH, Forfia P, Roger VL, Redfield MM. Right ventricular function in heart failure with preserved ejection fraction: a community-based study. Circulation 130: 2310-2320, 2014.

13. Iglesias-Garriz I, Olalla-Gómez C, Garrote C, López-Benito M, Martín J, Alonso D, Rodríguez MA. Contribution of right ventricular dysfunction to heart failure mortality: a metaanalysis. Rev Cardiovasc Med 13: e62-e69.

14. Melenovsky V, Hwang SJ, Lin G, Redfield MM, Borlaug BA. Right heart dysfunction in heart failure with preserved ejection fraction. Eur Heart J 35: 3452-3462, 2014.

15. Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, Dupuis J, Long CS, Rubin LJ, Smart FW, Suzuki YJ, Gladwin M, Denholm EM, Gail DB. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation 114: 1883-1891, 2006.

16. Katz AM, Rolett EL. Heart failure: when form fails to follow function. Eur Heart J 37: 449-454, 2016.

17. Santamore WP, Lynch PR, Heckman JL, Bove AA, Meier GD. Left ventricular effects on right ventricular developed pressure. J Appl Physiol 41: 925-930, 1976.

18. Dyke CM, Brunsting LA, Salter DR, Murphy CE, Abd-Elfattah A, Wechsler AS. Preload dependence of right ventricular blood flow: I. The normal right ventricle. Ann Thorac Surg 43: 478-483, 1987.

19. Do E, Baudet S, Verdys M, Touzeau C, Bailly F, Lucas-Héron B, Sagniez M, Rossi A, Noireaud J. Energy metabolism in normal and hypertrophied right ventricle of the ferret heart. J Mol Cell Cardiol 29: 1903-1913, 1997.

20. Gomez-Arroyo J, Mizuno S, Szczepanek K, Van Tassell B, Natarajan R, dos Remedios CG, Drake JI, Farkas L, Kraskauskas D, Wijesinghe DS, Chalfant CE, Bigbee J, Abbate A, Lesnefsky EJ, Bogaard HJ, Voelkel NF. Metabolic gene remodeling and mitochondrial dysfunction in failing right ventricular hypertrophy secondary to pulmonary arterial hypertension. Circ Heart Fail 6: 136-144, 2013.

21. Bishop JE, Rhodes S, Laurent GJ, Low RB, Stirewalt WS. Increased collagen synthesis and decreased collagen degradation in right ventricular hypertrophy induced by pressure overload. Cardiovasc Res 28: 1581-1585, 1994.

22. Piao L, Fang YH, Parikh KS, Ryan JJ, D'Souza KM, Theccanat T, Toth PT, Pogoriler J, Paul J, Blaxall BC, Akhter SA, Archer SL. GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension. Circulation 126: 2859-2869, 2012.

23. Maron BA, Leopold JA. The role of the renin-angiotensin-aldosterone system in the pathobiology of pulmonary arterial hypertension (2013 Grover Conference series). Pulm Circ 4: 200-210, 2014.

24. Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabé-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, Frisén J. Evidence for cardiomyocyte renewal in humans. Science 324: 98-102, 2009.

25. Hill JA, Olson EN. Cardiac plasticity. N Engl J Med 358: 1370-1380, 2008.

26. Maillet M, van Berlo JH, Molkentin JD. Molecular basis of physiological heart growth: fundamental concepts and new players. Nat Rev Mol Cell Biol 14: 38-48, 2013.

27. Laughlin MH, Bowles DK, Duncker DJ. The coronary circulation in exercise training. Am J Physiol Heart Circ Physiol 302: H10-H23, 2012.

28. Abel ED, Doenst T. Mitochondrial adaptations to physiological vs. pathological cardiac hypertrophy. Cardiovasc Res 90: 234-242, 2011.

29. Shimizu I, Minamino T. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol 97: 245-262, 2016.

30. Gerdes AM, Kellerman SE, Moore JA, Muffly KE, Clark LC, Reaves PY, Malec KB, McKeown PP, Schocken DD. Structural remodeling of cardiac myocytes in patients with ischemic cardiomyopathy. Circulation 86: 426-430, 1992.

31. Bernardo BC, Weeks KL, Pretorius L, McMullen JR. Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther 128: 191-227, 2010.

32. Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, Colucci WS, Walsh K. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest 115: 2108-2118, 2005.

33. Kang M, Chung KY, Walker JW. G-protein coupled receptor signaling in myocardium: not for the faint of heart. Physiology 22: 174-184, 2007.

34. Takimoto E. Cyclic GMP-dependent signaling in cardiac myocytes. Circ J 76: 1819-1825, 2012.

35. Riddle EL, Schwartzman RA, Bond M, Insel PA. Multi-tasking RGS proteins in the heart: the next therapeutic target? Circ Res 96: 401-411, 2005.

36. Zhang P, Mende U. Regulators of G-protein signaling in the heart and their potential as therapeutic targets. Circ Res 109: 320-333, 2011.

37. Takimoto E, Koitabashi N, Hsu S, Ketner EA, Zhang M, Nagayama T, Bedja D, Gabrielson KL, Blanton R, Siderovski DP, Mendelsohn ME, Kass DA. Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice. J Clin Invest 119: 408-420, 2009.

38. Tokudome T, Kishimoto I, Horio T, Arai Y, Schwenke DO, Hino J, Okano I, Kawano Y, Kohno M, Miyazato M, Nakao K, Kangawa K. Regulator of G-protein signaling subtype 4 mediates antihypertrophic effect of locally secreted natriuretic peptides in the heart. Circulation 117: 2329-2339, 2008.

39. Grossman W, Jones D, McLaurin LP. Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 56: 56-64, 1975.

40. Shah AM, Mann DL. In search of new therapeutic targets and strategies for heart failure: recent advances in basic science. Lancet 378: 704-712, 2011.

41. Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation 131: 550-559, 2015.

42. Whelan RS, Kaplinskiy V, Kitsis RN. Cell death in the pathogenesis of heart disease: mechanisms and significance. Annu Rev Physiol 72: 19-44, 2010.

43. Conrad CH, Brooks WW, Hayes JA, Sen S, Robinson KG, Bing OH. Myocardial fibrosis and stiffness with hypertrophy and heart failure in the spontaneously hypertensive rat. Circulation 91: 161-170, 1995.

44. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 322: 1561-1566, 1990.

45. Haider AW, Larson MG, Benjamin EJ, Levy D. Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death. J Am Coll Cardiol 32: 1454- 1459, 1998.

46. Klingbeil AU, Schneider M, Martus P, Messerli FH, Schmieder RE. A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension. Am J Med 115: 41- 46, 2003.

47. Pitt B, Reichek N, Willenbrock R, Zannad F, Phillips RA, Roniker B, Kleiman J, Krause S, Burns D, Williams GH. Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation 108: 1831-1838, 2003.

48. Wachtell K, Bella JN, Rokkedal J, Palmieri V, Papademetriou V, Dahlöf B, Aalto T, Gerdts E, Devereux RB. Change in diastolic left ventricular filling after one year of antihypertensive treatment: The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Circulation 105: 1071-1076, 2002.

49. Devereux RB, Palmieri V, Sharpe N, De Quattro V, Bella JN, de Simone G, Walker JF, Hahn RT, Dahlöf B. Effects of once-daily angiotensin-converting enzyme inhibition and calcium channel blockade-based antihypertensive treatment regimens on left ventricular hypertrophy and diastolic filling in hypertension: the prospective randomized enalapril study evaluating regression of ventricular enlargement (preserve) trial. Circulation 104: 1248-1254, 2001.

50. Solomon SD, Janardhanan R, Verma A, Bourgoun M, Daley WL, Purkayastha D, Lacourcière Y, Hippler SE, Fields H, Naqvi TZ, Mulvagh SL, Arnold JM, Thomas JD, Zile MR, Aurigemma GP. Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomised trial. Lancet 369: 2079-2087, 2007.

51. Barron AJ, Hughes AD, Sharp A, Baksi AJ, Surendran P, Jabbour RJ, Stanton A, Poulter N, Fitzgerald D, Sever P, O'Brien E, Thom S, Mayet J. Long-term antihypertensive treatment fails to improve E/e' despite regression of left ventricular mass: an AngloScandinavian cardiac outcomes trial substudy. Hypertension 63: 252-258, 2014.

52. Gupta A, Schiros CG, Gaddam KK, Aban I, Denney TS, Lloyd SG, Oparil S, Dell'Italia LJ, Calhoun DA, Gupta H. Effect of spironolactone on diastolic function in hypertensive left ventricular hypertrophy. J Hum Hypertens 29: 241-246, 2015.

53. Sharma K, Kass DA. Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ Res 115: 79-96, 2014.

54. Rodrigues PG, Leite-Moreira AF, Falcão-Pires I. Myocardial reverse remodeling: how far can we rewind? Am J Physiol Heart Circ Physiol 310: H1402-H1422, 2016.

55. Heinzel FR, Hohendanner F, Jin G, Sedej S, Edelmann F. Myocardial hypertrophy and its role in heart failure with preserved ejection fraction. J Appl Physiol 119: 1233-1242, 2015.

56. Shah SJ. Matchmaking for the optimization of clinical trials of heart failure with preserved ejection fraction: no laughing matter. J Am Coll Cardiol 62: 1339-1342, 2013.

57. Lim SL, Lam CS, Segers VF, Brutsaert DL, De Keulenaer GW. Cardiac endotheliummyocyte interaction: clinical opportunities for new heart failure therapies regardless of ejection fraction. Eur Heart J 36: 2050-2060, 2015.

58. Francis SH, Blount MA, Corbin JD. Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol Rev 91: 651-690, 2011.

59. Tsai EJ, Kass DA. Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics. Pharmacol Ther 122: 216-238, 2009.

60. Borlaug BA, Melenovsky V, Marhin T, Fitzgerald P, Kass DA. Sildenafil inhibits betaadrenergic-stimulated cardiac contractility in humans. Circulation 112: 2642-2649, 2005.

61. Nagayama T, Hsu S, Zhang M, Koitabashi N, Bedja D, Gabrielson KL, Takimoto E, Kass DA. Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload. J Am Coll Cardiol 53: 207-215, 2009.

62. Bishu K, Hamdani N, Mohammed SF, Kruger M, Ohtani T, Ogut O, Brozovich FV, Burnett JC Jr, Linke WA, Redfield MM. Sildenafil and B-type natriuretic peptide acutely phosphorylate titin and improve diastolic distensibility in vivo. Circulation 124: 2882-2891, 2011.

63. Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, St Aubin C, Webster L, Rebeyka IM, Ross DB, Light PE, Dyck JR, Michelakis ED. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation 116: 238-248, 2007.

64. Borgdorff MA, Bartelds B, Dickinson MG, Boersma B, Weij M, Zandvoort A, Silljé HH, Steendijk P, de Vroomen M, Berger RM. Sildenafil enhances systolic adaptation, but does not prevent diastolic dysfunction, in the pressure-loaded right ventricle. Eur J Heart Fail 14: 1067-1074, 2012.

65. Borgdorff MA, Bartelds B, Dickinson MG, van Wiechen MP, Steendijk P, de Vroomen M, Berger RM. Sildenafil treatment in established right ventricular dysfunction improves diastolic function and attenuates interstitial fibrosis independent from afterload. Am J Physiol Heart Circ Physiol 307: H361-H369, 2014.

66. Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 11: 214-222, 2005.

67. Schäfer S, Ellinghaus P, Janssen W, Kramer F, Lustig K, Milting H, Kast R, Klein M. Chronic inhibition of phosphodiesterase 5 does not prevent pressure-overload-induced rightventricular remodelling. Cardiovasc Res 82: 30-39, 2009.

68. Lewis GD, Shah R, Shahzad K, Camuso JM, Pappagianopoulos PP, Hung J, Tawakol A, Gerszten RE, Systrom DM, Bloch KD, Semigran MJ. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation 116: 1555-1562, 2007.

69. Guazzi M, Samaja M, Arena R, Vicenzi M, Guazzi MD. Long-term use of sildenafil in the therapeutic management of heart failure. J Am Coll Cardiol 50: 2136-2144, 2007.

70. Zhuang XD, Long M, Li F, Hu X, Liao XX, Du ZM. PDE5 inhibitor sildenafil in the treatment of heart failure: a meta-analysis of randomized controlled trials. Int J Cardiol 172: 581-587, 2014.

71. Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation 124: 164-174, 2011.

72. Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, LeWinter MM, Rouleau JL, Bull DA, Mann DL, Deswal A, Stevenson LW, Givertz MM, Ofili EO, O'Connor CM, Felker GM, Goldsmith SR, Bart BA, McNulty SE, Ibarra JC, Lin G, Oh JK, Patel MR, Kim RJ, Tracy RP, Velazquez EJ, Anstrom KJ, Hernandez AF, Mascette AM, Braunwald E; RELAX Trial. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 309: 1268-1277, 2013.

73. Hoendermis ES, Liu LC, Hummel YM, van der Meer P, de Boer RA, Berger RM, van Veldhuisen DJ, Voors AA. Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. Eur Heart J 36: 2565-2573, 2015.

74. Tanaka N, Dalton N, Mao L, Rockman HA, Peterson KL, Gottshall KR, Hunter JJ, Chien KR, Ross J Jr. Transthoracic echocardiography in models of cardiac disease in the mouse. Circulation 94: 1109-1117, 1996.

75. Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48: 452-458, 2013.

76. Chen Y, Guo H, Xu D, Xu X, Wang H, Hu X, Lu Z, Kwak D, Xu Y, Gunther R, Huo Y, Weir EK. Left ventricular failure produces profound lung remodeling and pulmonary hypertension in mice heart failure causes severe lung disease. Hypertension 59: 1170-1178, 2012.

77. Yasue H, Yoshimura M, Sumida H, Kikuta K, Kugiyama K, Jougasaki M, Ogawa H, Okumura K, Mukoyama M, Nakao K. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 90: 195-203, 1994.

78. Crilley JG, Farrer M. Left ventricular remodelling and brain natriuretic peptide after first myocardial infarction. Heart 86: 638-642, 2001.

79. Yang J, Rothermel B, Vega RB, Frey N, McKinsey TA, Olson EN, Bassel-Duby R, Williams RS. Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles. Circ Res 87: E61-E68, 2000.

80. Bueno OF, Molkentin JD. Involvement of extracellular signal-regulated kinases 1/2 in cardiac hypertrophy and cell death. Circ Res 91: 776-781, 2002.

81. Zou Y, Yao A, Zhu W, Kudoh S, Hiroi Y, Shimoyama M, Uozumi H, Kohmoto O, Takahashi T, Shibasaki F, Nagai R, Yazaki Y, Komuro I. Isoproterenol activates extracellular signal-regulated protein kinases in cardiomyocytes through calcineurin. Circulation 104: 102- 108, 2001.

82. Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest 135: 794-804, 2009.

83. Guihaire J, Noly PE, Schrepfer S, Mercier O. Advancing knowledge of right ventricular pathophysiology in chronic pressure overload: Insights from experimental studies. Arch Cardiovasc Dis 108: 519-529, 2015.

84. Reddy S, Bernstein D. Molecular Mechanisms of Right Ventricular Failure. Circulation 132: 1734-1742, 2015.

85. Ishikawa S, Honda M, Yamada S, Goto Y, Morioka S, Ishinaga Y, Murakami Y, Masumura S, Moriyama K. Different biventricular remodelling of myosin and collagen in pulmonary hypertension. Clin Exp Pharmacol Physiol 19: 723-732, 1992.

86. Sharma S, Taegtmeyer H, Adrogue J, Razeghi P, Sen S, Ngumbela K, Essop MF. Dynamic changes of gene expression in hypoxia-induced right ventricular hypertrophy. Am J Physiol Heart Circ Physiol 286: H1185-H1192, 2004.

87. Lourenço AP, Roncon-Albuquerque R Jr, Brás-Silva C, Faria B, Wieland J, Henriques-Coelho T, Correia-Pinto J, Leite-Moreira AF. Myocardial dysfunction and neurohumoral activation without remodeling in left ventricle of monocrotaline-induced pulmonary hypertensive rats. Am J Physiol Heart Circ Physiol 291: H1587-H1594, 2006.

88. Wilson DW, Segall HJ, Pan LC, Dunston SK. Progressive inflammatory and structural changes in the pulmonary vasculature of monocrotaline-treated rats. Microvasc Res 38: 57-80, 1989.

89. Eltzschig HK, Carmeliet P. Hypoxia and inflammation. N Engl J Med 364: 656-665, 2011.

90. Cho H, Harrison K, Schwartz O, Kehrl JH. The aorta and heart differentially express RGS (regulators of G-protein signalling) proteins that selectively regulate sphingosine 1- phosphate, angiotensin II and endothelin-1 signalling. Biochem J 371: 973-980, 2003.

91. Chatterjee TK, Fisher RA. Cytoplasmic, nuclear, and golgi localization of RGS proteins. Evidence for N-terminal and RGS domain sequences as intracellular targeting motifs. J Biol Chem 275: 24013-24021, 2000.

92. Heximer SP, Lim H, Bernard JL, Blumer KJ. Mechanisms governing subcellular localization and function of human RGS2. J Biol Chem 276: 14195-14203, 2001.

93. Roy AA, Lemberg KE, Chidiac P. Recruitment of RGS2 and RGS4 to the plasma membrane by G proteins and receptors reflects functional interactions. Mol Pharmacol 64: 587- 593, 2003.

94. Tang KM, Wang GR, Lu P, Karas RH, Aronovitz M, Heximer SP, Kaltenbronn KM, Blumer KJ, Siderovski DP, Zhu Y, Mendelsohn ME. Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nat Med 9: 1506-1512, 2003.

95. Pedram A, Razandi M, Kehrl J, Levin ER. Natriuretic peptides inhibit G protein activation. Mediation through cross-talk between cyclic GMP-dependent protein kinase and regulators of G protein-signaling proteins. J Biol Chem 275: 7365-7372, 2000.

96. Nagayama T, Hsu S, Zhang M, Koitabashi N, Bedja D, Gabrielson KL, Takimoto E, Kass DA. Pressure-overload magnitude-dependence of the anti-hypertrophic efficacy of PDE5A inhibition. J Mol Cell Cardiol 46: 560-567, 2009.

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