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CPU86017 and its isomers improve hypoxic pulmonary hypertension by attenuating increased ETA receptor expression and extracellular matrix accumulation

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Abstract

Remodeling of the pulmonary artery is a major feature of pulmonary artery hypertension, and CPU86017, a derivative of berberine, is known to effectively alleviate hypoxic pulmonary hypertension (HPH). CPU86017 is a racemate, possessing two chiral centers: 7N and 13aC. We have compared the effects of four CPU86017 isomers, SS [(+)-7S, 13aS-CPU86017], SR [(-)-7S, 13aR-CPU86017], RR [(-)-7R, 13aR-CPU86017] and RS [(+)-7R, 13aS-CPU86017], on HPH. Sprague-Dawley rats were exposed to hypoxic conditions (10 ± 0.5% O2 for 8 h per day) for 4 weeks and treated with CPU86017, SS, SR, RR or RS (4 mg/kg, subcutaneously) from day 15 to 28. After 4 weeks of exposure to hypoxia, remodeling of the right ventricle and the small pulmonary arteries (<150 μm) was very pronounced, and extra-cellular matrix (ECM) had been excessively produced in association with abnormal mRNA and protein expression of matrix metalloproteinase 9 (MMP9) and mRNA of tissue inhibitor of matrix metalloproteinase 1 and 2 (TIMP1, TIMP2). Expression of endothelin receptor A was upregulated, while that connexin 40 was downregulated. The administration of CPU86017 and its four isomers attenuated the changes, with the isomer RS exhibiting the most favorable effect on HPH rats. We propose that an activated endothelin pathway associated with an unbalanced MMP–TIMP system may contribute to the over-accumulation of ECM and the remodeling of the pulmonary arterioles in HPH. CPU86017 and its four isomers attenuate ECM accumulation and vascular remodeling by normalizing both the MMP–TIMP system and the ET system. The RS isomer is superior to the racemate CPU86017 in attenuating HPH.

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Abbreviations

CVP:

central venous pressure

Cx40:

connexin 40

dp/dtmax:

maximum velocity of right ventricular systole

dp/dtmin:

maximum velocity of right ventricular diastole

EC:

endothelial cell

ECM:

extra-cellular matrix

ET-1:

endothelin-1

ETAR:

endothelin receptor A

HPH:

hypoxic pulmonary hypertension

MMP:

matrix metalloproteinase

PAH:

pulmonary arterial hypertension

PVSMC:

pulmonary vascular smooth muscle cell

ROS:

reactive oxidative species

RV/BW:

right ventricular weight/body weight

RV/LV+S:

right ventricle/(left ventricle + septum)

RVEDP:

right ventricular end-diastolic pressure

RVSP:

right ventricular systolic pressure

SMC:

smooth muscle cell

TIMP:

tissue inhibitor of matrix metalloproteinase

WT:

wall thickness

References

  • Andersen CU, Mulvany MJ, Simonsen U (2005) Lack of synergistic effect of molsidomine and sildenafil on development of pulmonary hypertension in chronic hypoxic rats. Eur J Pharmacol 510:87–96

    Article  PubMed  CAS  Google Scholar 

  • Ammarguellat FZ, Gannon PO, Amiri F, Schiffrin EL (2002) Fibrosis, matrix metalloproteinases, and inflammation in the heart of DOCA-salt hypertensive rats: role of ET(A) receptors. Hypertension 39:679–684

    Article  PubMed  CAS  Google Scholar 

  • Atkinson JJ, Senior RM (2003) Matrix metalloproteinase-9 in lung remodeling. Am J Respir Cell Mol Biol 28:12–24

    Article  PubMed  CAS  Google Scholar 

  • Bonnet S, Archer SL (2007) Potassium channel diversity in the pulmonary arteries and pulmonary veins: implications for regulation of the pulmonary vasculature in health and during pulmonary hypertension. Pharmacol Ther 115:56–69

    Article  PubMed  CAS  Google Scholar 

  • Budhiraja R, Tuder RM, Hassoun PM (2004) Endothelial dysfunction in pulmonary hypertension. Circulation 109:159–165

    Article  PubMed  Google Scholar 

  • Burg ED, Remillard CV, Yuan JX (2008) Potassium channels in the regulation of pulmonary artery smooth muscle cell proliferation and apoptosis: pharmacotherapeutic implications. Br J Pharmacol 153[Suppl 1]:S99–S111

    Article  PubMed  CAS  Google Scholar 

  • Cozzi F, Montisci R, Marotta H, Bobbo F, Durigon N, Ruscazio M, Sfriso P, Iliceto S, Todesco S (2006) Bosentan therapy of pulmonary arterial hypertension in connective tissue diseases. Eur J Clin Invest 36[Suppl 3]:49–53

    Article  PubMed  CAS  Google Scholar 

  • Cui B, Yu F, Dai DZ, Zhang TT, Tang XY, Dai Y (2007) CPU0123, a novel endothelin receptor antagonist, relieves hypoxic pulmonary hypertension in rats by suppressing excessive ET-ROS pathway. Drug Dev Res 68:42–50

    Article  CAS  Google Scholar 

  • Dai DZ (2006) CPU86017: a novel Class III antiarrhythmic agent with multiple actions at ion channels. Cardiovasc Drug Rev 24:101–115

    Article  PubMed  CAS  Google Scholar 

  • Dawes KE, Cambrey AD, Campa JS, Bishop JE, McAnulty RJ, Peacock AJ, Laurent GJ (1996) Changes in collagen metabolism in response to endothelin-1: evidence for fibroblast heterogeneity. Int J Biochem Cell Biol 28:229–238

    Article  PubMed  CAS  Google Scholar 

  • de Wit C, Roos F, Bolz SS, Kirchhoff S, Kruger O, Willecke K, Pohl U (2000) Impaired conduction of vasodilation along arterioles in connexin40-deficient mice. Circ Res 86:649–655

    PubMed  Google Scholar 

  • Felx M, Guyot MC, Isler M, Turcotte RE, Doyon J, Khatib AM, Leclerc S, Moreau A, Moldovan F (2006) Endothelin-1 (ET-1) promotes MMP-2 and MMP-9 induction involving the transcription factor NF-kappaB in human osteosarcoma. Clin Sci (Lond) 110:645–654

    Article  CAS  Google Scholar 

  • Giannelli G, Iannone F, Marinosci F, Lapadula G, Antonaci S (2006) Clinical outcomes of bosentan in pulmonary arterial hypertension do not correlate with levels of TIMPs. Eur J Clin Invest 36[Suppl 3]:73–77

    Article  PubMed  CAS  Google Scholar 

  • Jozwiak Z, Marczak A (2006) The role of ion channels in apoptosis. Postepy Biochem 52:373–382

    PubMed  CAS  Google Scholar 

  • Kamezaki F, Tasaki H, Yamashita K, Tsutsui M, Koide S, Nakata S, Tanimoto A, Okazaki M, Sasaguri Y, Adachi T, Otsuji Y (2008) Gene transfer of extracellular superoxide dismutase ameliorates pulmonary hypertension in rats. Am J Respir Crit Care Med 177:219–226

    Article  PubMed  CAS  Google Scholar 

  • Kasi VS, Xiao HD, Shang LL, Iravanian S, Langberg J, Witham EA, Jiao Z, Gallego CJ, Bernstein KE, Dudley SC Jr (2007) Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation. Am J Physiol Heart Circ Physiol 293:H182–H192

    Article  PubMed  CAS  Google Scholar 

  • Ko YS, Yeh HI, Rothery S, Dupont E, Coppen SR, Severs NJ (1999) Connexin make-up of endothelial gap junctions in the rat pulmonary artery as revealed by immunoconfocal microscopy and triple-label immunogold electron microscopy. J Histochem Cytochem 47:683–691

    PubMed  CAS  Google Scholar 

  • Krattinger N, Capponi A, Mazzolai L, Aubert JF, Caille D, Nicod P, Waeber G, Meda P, Haefliger JA (2007) Connexin40 regulates renin production and blood pressure. Kidney Int 72:814–822

    Article  PubMed  CAS  Google Scholar 

  • Kulig K, Nowicki P, Malawska B (2004) Influence of the absolute configuration on pharmacological activity of antihypertensive and antiarrhythmic drugs. Pol J Pharmacol 56:499–508

    PubMed  CAS  Google Scholar 

  • Kunzmann S, Schmidt-Weber C, Zingg JM, Azzi A, Kramer BW, Blaser K, Akdis CA, Speer CP (2007) Connective tissue growth factor expression is regulated by histamine in lung fibroblasts: potential role of histamine in airway remodeling. J Allergy Clin Immunol 119:1398–1407

    Article  PubMed  CAS  Google Scholar 

  • Lee KM, Tsai KY, Wang N, Ingber DE (1998) Extracellular matrix and pulmonary hypertension: control of vascular smooth muscle cell contractility. Am J Physiol 274:H76–H82

    PubMed  CAS  Google Scholar 

  • Lepetit H, Eddahibi S, Fadel E, Frisdal E, Munaut C, Noel A, Humbert M, Adnot S, D’Ortho MP, Lafuma C (2005) Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension. Eur Respir J 25:834–842

    Article  PubMed  CAS  Google Scholar 

  • Li N, Yang L, Dai DZ, Wang QJ, Dai Y (2008) Chiral separation of racemate CPU86017, an anti-arrhythmic agent, produces stereoisomers possessing favourable ion channel blockade and less alpha-adrenoceptor antagonism. Clin Exp Pharmacol Physiol 35:643–650

    Article  PubMed  CAS  Google Scholar 

  • Lin MJ, Yang XR, Cao YN, Sham JS (2007) Hydrogen peroxide-induced Ca2+ mobilization in pulmonary arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 292:L1598–L1608

    Article  PubMed  CAS  Google Scholar 

  • Liu Q, Dai DZ (2004) Influence of a new endothelin receptor antagonist CPU-0213 on expression of MMPs mRNA and TIMPs mRNA in rats with hypertrophic myocardium induced by L-thyroxin. Chinese J Clin Pharmacol Therapeut 35:150–155

    CAS  Google Scholar 

  • Mandegar M, Yuan JX (2002) Role of K+ channels in pulmonary hypertension. Vascul Pharmacol 38:25–33

    Article  PubMed  CAS  Google Scholar 

  • Merklinger SL, Jones PL, Martinez EC, Rabinovitch M (2005) Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 112:423–431

    Article  PubMed  CAS  Google Scholar 

  • Moudgil R, Michelakis ED, Archer SL (2006) The role of k+ channels in determining pulmonary vascular tone, oxygen sensing, cell proliferation, and apoptosis: implications in hypoxic pulmonary vasoconstriction and pulmonary arterial hypertension. Microcirculation 13:615–632

    Article  PubMed  CAS  Google Scholar 

  • Podesser BK, Siwik DA, Eberli FR, Sam F, Ngoy S, Lambert J, Ngo K, Apstein CS, Colucci WS (2001) ETA-receptor blockade prevents matrix metalloproteinase activation late postmyocardial infarction in the rat. Am J Physiol Heart Circ Physiol 280:H984–H991

    PubMed  CAS  Google Scholar 

  • Quinn DA, Du HK, Thompson BT, Hales CA (1998) Amiloride analogs inhibit chronic hypoxic pulmonary hypertension. Am J Respir Crit Care Med 157:1263–1268

    PubMed  CAS  Google Scholar 

  • Rennard SI, Togo S, Holz O (2006) Cigarette smoke inhibits alveolar repair: a mechanism for the development of emphysema. Proc Am Thorac Soc 3:703–708

    Article  PubMed  CAS  Google Scholar 

  • Ruiz V, Ordonez RM, Berumen J, Ramirez R, Uhal B, Becerril C, Pardo A, Selman M (2003) Unbalanced collagenases/TIMP-1 expression and epithelial apoptosis in experimental lung fibrosis. Am J Physiol Lung Cell Mol Physiol 285:L1026–L1036

    PubMed  CAS  Google Scholar 

  • Simi L, Andreani M, Davini F, Janni A, Pazzagli M, Serio M, Orlando C (2004) Simultaneous measurement of MMP9 and TIMP1 mRNA in human non small cell lung cancers by multiplexreal time RT-PCR. Lung Cancer 45:171–179

    Article  PubMed  Google Scholar 

  • Simon AM, McWhorter AR (2002) Vascular abnormalities in mice lacking the endothelial gap junction proteins connexin37 and connexin40. Dev Biol 251:206–220

    Article  PubMed  CAS  Google Scholar 

  • Smirnov SV, Robertson TP, Ward JP, Aaronson PI (1994) Chronic hypoxia is associated with reduced delayed rectifier K+ current in rat pulmonary artery muscle cells. Am J Physiol 266:H365–H370

    PubMed  CAS  Google Scholar 

  • Sun R, Yan Y, Chen X, Si Q, Li H (1994) Role of collagen metabolism changes in the pathogenesis of pulmonary hypertension in rats and its reversibility. Chin Med Sci J 9:183–186

    PubMed  CAS  Google Scholar 

  • Townsley MI, King JA, Alvarez DF (2006) Ca2+ channels and pulmonary endothelial permeability: insights from study of intact lung and chronic pulmonary hypertension. Microcirculation 13:725–739

    Article  PubMed  CAS  Google Scholar 

  • Tozzi CA, Christiansen DL, Poiani GJ, Riley DJ (1994) Excess collagen in hypertensive pulmonary arteries decreases vascular distensibility. Am J Respir Crit Care Med 149:1317–1326

    PubMed  CAS  Google Scholar 

  • Vieillard-Baron A, Frisdal E, Eddahibi S, Deprez I, Baker AH, Newby AC, Berger P, Levame M, Raffestin B, Adnot S, d’Ortho MP (2000) Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer or doxycycline aggravates pulmonary hypertension in rats. Circ Res 87:418–425

    PubMed  CAS  Google Scholar 

  • Wang HL, Dai DZ, Gao E, Zhang YP, Lu F (2004) Dispersion of ventricular mRNA of RyR2 and SERCA2 associated with arrhythmogenesis in rats. Acta Pharmacol Sin 25:738–743

    PubMed  CAS  Google Scholar 

  • Xia HJ, Dai DZ, Dai Y (2006) Up-regulated inflammatory factors endothelin, NFkappaB, TNFalpha and iNOS involved in exaggerated cardiac arrhythmias in l-thyroxine-induced cardiomyopathy are suppressed by darusentan in rats. Life Sci 79:1812–1819

    Article  PubMed  CAS  Google Scholar 

  • Xu FP, Chen MS, Wang YZ, Yi Q, Lin SB, Chen AF, Luo JD (2004a) Leptin induces hypertrophy via endothelin-1-reactive oxygen species pathway in cultured neonatal rat cardiomyocytes. Circulation 110:1269–1275

    Article  PubMed  CAS  Google Scholar 

  • Xu SW, Howat SL, Renzoni EA, Holmes A, Pearson JD, Dashwood MR, Bou-Gharios G, Denton CP, du Bois RM, Black CM, Leask A, Abraham DJ (2004b) Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK. J Biol Chem 279:23098–23103

    Article  PubMed  CAS  Google Scholar 

  • Yeh HI, Lai YJ, Chang HM, Ko YS, Severs NJ, Tsai CH (2000) Multiple connexin expression in regenerating arterial endothelial gap junctions. Arterioscler Thromb Vasc Biol 20:1753–1762

    PubMed  CAS  Google Scholar 

  • Yuan SH, Li N, Dai DZ (2006) Vasomotor of pulmonary and tail arteries from two pulmonary hypertension rat models and in vitro drug intervention. Progr Pharm Sci (Chinese) 30:314–321

    CAS  Google Scholar 

  • Zhang S, Dong H, Rubin LJ, Yuan JX (2007) Upregulation of Na+/Ca2+ exchanger contributes to the enhanced Ca2+ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. Am J Physiol Cell Physiol 292:C2297–C2305

    Article  PubMed  CAS  Google Scholar 

  • Zhang TT, Cui B, Dai DZ, Su W (2005a) CPU 86017, p-chlorobenzyltetrahydroberberine chloride, attenuates monocrotaline-induced pulmonary hypertension by suppressing endothelin pathway. Acta Pharmacol Sin 26:1309–1316

    Article  PubMed  CAS  Google Scholar 

  • Zhang TT, Cui B, Dai DZ, Tang XY (2005b) Pharmacological efficacy of CPU 86017 on hypoxic pulmonary hypertension in rats: mediated by direct inhibition of calcium channels and antioxidant action, but indirect effects on the ET-1 pathway. J Cardiovasc Pharmacol 46:727–734

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study is supported by the key project of the National Basic Research Program of China (973 Programs: 2007CB512000/2007CB512006, to BF Yang).

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  1. Research Division of Pharmacology, China Pharmaceutical University, 24 Tongjia Lane, Nanjing, 210009, China

    Na Li, De-Zai Dai & Yin Dai

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  1. Na Li
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Correspondence to De-Zai Dai.

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Li, N., Dai, DZ. & Dai, Y. CPU86017 and its isomers improve hypoxic pulmonary hypertension by attenuating increased ETA receptor expression and extracellular matrix accumulation. Naunyn-Schmied Arch Pharmacol 378, 541–552 (2008). https://doi.org/10.1007/s00210-008-0309-4

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  • DOI: https://doi.org/10.1007/s00210-008-0309-4

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