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01-11-2011 | Original Contribution

Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart

Authors: Clint L. Miller, Yujun Cai, Masayoshi Oikawa, Tamlyn Thomas, Wolfgang R. Dostmann, Manuela Zaccolo, Keigi Fujiwara, Chen Yan

Published in: Basic Research in Cardiology | Issue 6/2011

Abstract

Cardiac fibroblasts become activated and differentiate to smooth muscle-like myofibroblasts in response to hypertension and myocardial infarction (MI), resulting in extracellular matrix (ECM) remodeling, scar formation and impaired cardiac function. cAMP and cGMP-dependent signaling have been implicated in cardiac fibroblast activation and ECM synthesis. Dysregulation of cyclic nucleotide phosphodiesterase (PDE) activity/expression is also associated with various diseases and several PDE inhibitors are currently available or in development for treating these pathological conditions. The objective of this study is to define and characterize the specific PDE isoform that is altered during cardiac fibroblast activation and functionally important for regulating myofibroblast activation and ECM synthesis. We have found that Ca²⁺/calmodulin-stimulated PDE1A isoform is specifically induced in activated cardiac myofibroblasts stimulated by Ang II and TGF-β in vitro as well as in vivo within fibrotic regions of mouse, rat, and human diseased hearts. Inhibition of PDE1A function via PDE1-selective inhibitor or PDE1A shRNA significantly reduced Ang II or TGF-β-induced myofibroblast activation, ECM synthesis, and pro-fibrotic gene expression in rat cardiac fibroblasts. Moreover, the PDE1 inhibitor attenuated isoproterenol-induced interstitial fibrosis in mice. Mechanistic studies revealed that PDE1A modulates unique pools of cAMP and cGMP, predominantly in perinuclear and nuclear regions of cardiac fibroblasts. Further, both cAMP-Epac-Rap1 and cGMP-PKG signaling was involved in PDE1A-mediated regulation of collagen synthesis. These results suggest that induction of PDE1A plays a critical role in cardiac fibroblast activation and cardiac fibrosis, and targeting PDE1A may lead to regression of the adverse cardiac remodeling associated with various cardiac diseases.

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Aizawa T, Wei H, Miano JM, Abe J, Berk BC, Yan C (2003) Role of phosphodiesterase 3 in NO/cGMP-mediated antiinflammatory effects in vascular smooth muscle cells. Circ Res 93:406–413. doi:10.1161/01.RES.0000091074.33584.F0 PubMedCrossRef

Andric SA, Kostic TS, Stojilkovic SS (2006) Contribution of multidrug resistance protein MRP5 in control of cyclic guanosine 5′-monophosphate intracellular signaling in anterior pituitary cells. Endocrinology 147:3435–3445. doi:10.1210/en.2006-0091 PubMedCrossRef

Batchelor AM, Bartus K, Reynell C, Constantinou S, Halvey EJ, Held KF, Dostmann WR, Vernon J, Garthwaite J (2010) Exquisite sensitivity to subsecond, picomolar nitric oxide transients conferred on cells by guanylyl cyclase-coupled receptors. Proc Natl Acad Sci USA 107:22060–22065. doi:10.1073/pnas.1013147107 PubMedCrossRef

Bax NA, van Oorschot AA, Maas S, Braun J, van Tuyn J, de Vries AA, Groot AC, Goumans MJ (2011) In vitro epithelial-to-mesenchymal transformation in human adult epicardial cells is regulated by TGFbeta-signaling and WT1. Basic Res Cardiol 106:829–847. doi:10.1007/s00395-011-0181-0 PubMedCrossRef

Beavo JA, Brunton LL (2002) Cyclic nucleotide research—still expanding after half a century. Nat Rev Mol Cell Biol 3:710–718. doi:10.1038/nrm911 PubMedCrossRef

Beavo JA, Hardman JG, Sutherland EW (1970) Hydrolysis of cyclic guanosine and adenosine 3′, 5′-monophosphates by rat and bovine tissues. J Biol Chem 245:5649–5655PubMed

Berk BC, Fujiwara K, Lehoux S (2007) ECM remodeling in hypertensive heart disease. J Clin Invest 117:568–575. doi:10.1172/JCI31044 PubMedCrossRef

Bode DC, Kanter JR, Brunton LL (1991) Cellular distribution of phosphodiesterase isoforms in rat cardiac tissue. Circ Res 68:1070–1079PubMed

Brown RD, Ambler SK, Mitchell MD, Long CS (2005) The cardiac fibroblast: therapeutic target in myocardial remodeling and failure. Annu Rev Pharmacol Toxicol 45:657–687. doi:10.1146/annurev.pharmtox.45.120403.095802 PubMedCrossRef

10.

Butt E, Pohler D, Genieser HG, Huggins JP, Bucher B (1995) Inhibition of cyclic GMP-dependent protein kinase-mediated effects by (Rp)-8-bromo-PET-cyclic GMPS. Br J Pharmacol 116:3110–3116PubMed

11.

Cai Y, Miller CL, Nagel DJ, Jeon KI, Lim S, Gao P, Knight PA, Yan C (2011) Cyclic nucleotide phosphodiesterase 1 regulates lysosome-dependent type I collagen protein degradation in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 31:616–623. doi:10.1161/atvbaha.110.212621 PubMedCrossRef

12.

Calderone A, Thaik CM, Takahashi N, Chang DL, Colucci WS (1998) Nitric oxide, atrial natriuretic peptide, and cyclic GMP inhibit the growth-promoting effects of norepinephrine in cardiac myocytes and fibroblasts. J Clin Invest 101:812–818. doi:10.1172/JCI119883 PubMedCrossRef

13.

Castoldi G, Di Gioia CR, Pieruzzi F, D’Orlando C, Van De Greef WM, Busca G, Sperti G, Stella A (2003) ANG II increases TIMP-1 expression in rat aortic smooth muscle cells in vivo. Am J Physiol Heart Circ Physiol 284:H635–H643. doi:10.1152/ajpheart.00986.2001 PubMed

14.

Castro LR, Schittl J, Fischmeister R (2010) Feedback control through cGMP-dependent protein kinase contributes to differential regulation and compartmentation of cGMP in rat cardiac myocytes. Circ Res 107:1232–1240. doi:10.1161/circresaha.110.226712 PubMedCrossRef

15.

Chorianopoulos E, Heger T, Lutz M, Frank D, Bea F, Katus HA, Frey N (2010) FGF-inducible 14-kDa protein (Fn14) is regulated via the RhoA/ROCK kinase pathway in cardiomyocytes and mediates nuclear factor-kappaB activation by TWEAK. Basic Res Cardiol 105:301–313. doi:10.1007/s00395-009-0046-y PubMedCrossRef

16.

Ding B, Abe J, Wei H, Huang Q, Walsh RA, Molina CA, Zhao A, Sadoshima J, Blaxall BC, Berk BC, Yan C (2005) Functional role of phosphodiesterase 3 in cardiomyocyte apoptosis: implication in heart failure. Circulation 111:2469–2476. doi:10.1161/01.CIR.0000165128.39715.87 PubMedCrossRef

17.

DiPilato LM, Cheng X, Zhang J (2004) Fluorescent indicators of cAMP and Epac activation reveal differential dynamics of cAMP signaling within discrete subcellular compartments. Proc Natl Acad Sci U S A 101:16513–16518. doi:10.1073/pnas.0405973101 PubMedCrossRef

18.

Dostmann WR, Taylor MS, Nickl CK, Brayden JE, Frank R, Tegge WJ (2000) Highly specific, membrane-permeant peptide blockers of cGMP-dependent protein kinase Ialpha inhibit NO-induced cerebral dilation. Proc Natl Acad Sci USA 97:14772–14777. doi:10.1073/pnas.97.26.14772 PubMedCrossRef

19.

Doyle DD, Upshaw-Earley J, Bell EL, Palfrey HC (2002) Natriuretic peptide receptor-B in adult rat ventricle is predominantly confined to the nonmyocyte population. Am J Physiol Heart Circ Physiol 282:H2117–H2123. doi:10.1152/ajpheart.00988.2001 PubMed

20.

Drake MT, Violin JD, Whalen EJ, Wisler JW, Shenoy SK, Lefkowitz RJ (2008) beta-arrestin-biased agonism at the beta2-adrenergic receptor. J Biol Chem 283:5669–5676. doi:10.1074/jbc.M708118200 PubMedCrossRef

21.

Fischmeister R, Castro LR, Abi-Gerges A, Rochais F, Jurevicius J, Leroy J, Vandecasteele G (2006) Compartmentation of cyclic nucleotide signaling in the heart: the role of cyclic nucleotide phosphodiesterases. Circ Res 99:816–828. doi:10.1161/01.RES.0000246118.98832.04 PubMedCrossRef

22.

Giasson E, Servant MJ, Meloche S (1997) Cyclic AMP-mediated inhibition of angiotensin II-induced protein synthesis is associated with suppression of tyrosine phosphorylation signaling in vascular smooth muscle cells. J Biol Chem 272:26879–26886PubMedCrossRef

23.

Hammoud L, Lu X, Lei M, Feng Q (2011) Deficiency in TIMP-3 increases cardiac rupture and mortality post-myocardial infarction via EGFR signaling: beneficial effects of cetuximab. Basic Res Cardiol 106:459–471. doi:10.1007/s00395-010-0147-7 PubMedCrossRef

24.

Hao Y, Xu N, Box AC, Schaefer L, Kannan K, Zhang Y, Florens L, Seidel C, Washburn MP, Wiegraebe W, Mak HY (2011) Nuclear cGMP-dependent kinase regulates gene expression via activity-dependent recruitment of a conserved histone deacetylase complex. PLoS Genet 7:e1002065. doi:10.1371/journal.pgen.1002065 PubMedCrossRef

25.

Haworth RS, Cuello F, Avkiran M (2011) Regulation by phosphodiesterase isoforms of protein kinase A-mediated attenuation of myocardial protein kinase D activation. Basic Res Cardiol 106:51–63. doi:10.1007/s00395-010-0116-1 PubMedCrossRef

26.

Jeon KI, Jono H, Miller CL, Cai Y, Lim S, Liu X, Gao P, Abe J, Li JD, Yan C (2010) Ca2⁺/calmodulin-stimulated PDE1 regulates the beta-catenin/TCF signaling through PP2A B56 gamma subunit in proliferating vascular smooth muscle cells. FEBS J 277:5026–5039. doi:10.1111/j.1742-4658.2010.07908.x PubMedCrossRef

27.

Kim D, Rybalkin SD, Pi X, Wang Y, Zhang C, Munzel T, Beavo JA, Berk BC, Yan C (2001) Upregulation of phosphodiesterase 1A1 expression is associated with the development of nitrate tolerance. Circulation 104:2338–2343PubMedCrossRef

28.

Kim HE, Dalal SS, Young E, Legato MJ, Weisfeldt ML, D’Armiento J (2000) Disruption of the myocardial extracellular matrix leads to cardiac dysfunction. J Clin Invest 106:857–866. doi:10.1172/jci8040 PubMedCrossRef

29.

Kim NN, Villegas S, Summerour SR, Villarreal FJ (1999) Regulation of cardiac fibroblast extracellular matrix production by bradykinin and nitric oxide. J Mol Cell Cardiol 31:457–466. doi:10.1006/jmcc.1998.0887 PubMedCrossRef

30.

Klaiber M, Kruse M, Volker K, Schroter J, Feil R, Freichel M, Gerling A, Feil S, Dietrich A, Londono JE, Baba HA, Abramowitz J, Birnbaumer L, Penninger JM, Pongs O, Kuhn M (2010) Novel insights into the mechanisms mediating the local antihypertrophic effects of cardiac atrial natriuretic peptide: role of cGMP-dependent protein kinase and RGS2. Basic Res Cardiol 105:583–595. doi:10.1007/s00395-010-0098-z PubMedCrossRef

31.

Koutalos Y, Nakatani K, Yau KW (1995) Cyclic GMP diffusion coefficient in rod photoreceptor outer segments. Biophys J 68:373–382. doi:10.1016/s0006-3495(95)80198-0 PubMedCrossRef

32.

Leask A, Abraham DJ (2004) TGF-beta signaling and the fibrotic response. FASEB J 18:816–827. doi:10.1096/fj.03-1273rev PubMedCrossRef

33.

Lee DI, Vahebi S, Tocchetti CG, Barouch LA, Solaro RJ, Takimoto E, Kass DA (2010) PDE5A suppression of acute beta-adrenergic activation requires modulation of myocyte beta-3 signaling coupled to PKG-mediated troponin I phosphorylation. Basic Res Cardiol 105:337–347. doi:10.1007/s00395-010-0084-5 PubMedCrossRef

34.

Leineweber K, Bohm M, Heusch G (2006) Cyclic adenosine monophosphate in acute myocardial infarction with heart failure: slayer or savior? Circulation 114:365–367. doi:10.1161/circulationaha.106.642132 PubMedCrossRef

35.

Li P, Wang D, Lucas J, Oparil S, Xing D, Cao X, Novak L, Renfrow MB, Chen YF (2008) Atrial natriuretic peptide inhibits transforming growth factor beta-induced Smad signaling and myofibroblast transformation in mouse cardiac fibroblasts. Circ Res 102:185–192. doi:10.1161/CIRCRESAHA.107.157677 PubMedCrossRef

36.

Lukowski R, Rybalkin SD, Loga F, Leiss V, Beavo JA, Hofmann F (2010) Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes. Proc Natl Acad Sci USA 107:5646–5651. doi:10.1073/pnas.1001360107 PubMedCrossRef

37.

Masuyama H, Tsuruda T, Kato J, Imamura T, Asada Y, Stasch JP, Kitamura K, Eto T (2006) Soluble guanylate cyclase stimulation on cardiovascular remodeling in angiotensin II-induced hypertensive rats. Hypertension 48:972–978. doi:10.1161/01.HYP.0000241087.12492.47 PubMedCrossRef

38.

Miller CL, Oikawa M, Cai Y, Wojtovich AP, Nagel DJ, Xu X, Xu H, Florio V, Rybalkin SD, Beavo JA, Chen YF, Li JD, Blaxall BC, Abe J, Yan C (2009) Role of Ca2 +/calmodulin-stimulated cyclic nucleotide phosphodiesterase 1 in mediating cardiomyocyte hypertrophy. Circ Res 105:956–964. doi:10.1161/CIRCRESAHA.109.198515 PubMedCrossRef

39.

Nagel DJ, Aizawa T, Jeon KI, Liu W, Mohan A, Wei H, Miano JM, Florio VA, Gao P, Korshunov VA, Berk BC, Yan C (2006) Role of nuclear Ca2 +/calmodulin-stimulated phosphodiesterase 1A in vascular smooth muscle cell growth and survival. Circ Res 98:777–784. doi:10.1161/01.RES.0000215576.27615.fd PubMedCrossRef

40.

Nakamura H, Isaka Y, Tsujie M, Rupprecht HD, Akagi Y, Ueda N, Imai E, Hori M (2002) Introduction of DNA enzyme for Egr-1 into tubulointerstitial fibroblasts by electroporation reduced interstitial alpha-smooth muscle actin expression and fibrosis in unilateral ureteral obstruction (UUO) rats. Gene Ther 9:495–502. doi:10.1038/sj.gt.3301681 PubMedCrossRef

41.

Nausch LW, Ledoux J, Bonev AD, Nelson MT, Dostmann WR (2008) Differential patterning of cGMP in vascular smooth muscle cells revealed by single GFP-linked biosensors. Proc Natl Acad Sci USA 105:365–370. doi:10.1073/pnas.0710387105 PubMedCrossRef

42.

Nikolaev VO, Bunemann M, Hein L, Hannawacker A, Lohse MJ (2004) Novel single chain cAMP sensors for receptor-induced signal propagation. J Biol Chem 279:37215–37218. doi:10.1074/jbc.C400302200 PubMedCrossRef

43.

Nikolaev VO, Lohse MJ (2006) Monitoring of cAMP synthesis and degradation in living cells. Physiology (Bethesda) 21:86–92. doi:10.1152/physiol.00057.2005 CrossRef

44.

Oerlemans MI, Goumans MJ, van Middelaar B, Clevers H, Doevendans PA, Sluijter JP (2010) Active Wnt signaling in response to cardiac injury. Basic Res Cardiol 105:631–641. doi:10.1007/s00395-010-0100-9 PubMedCrossRef

45.

Ostrom RS, Naugle JE, Hase M, Gregorian C, Swaney JS, Insel PA, Brunton LL, Meszaros JG (2003) Angiotensin II enhances adenylyl cyclase signaling via Ca2 +/calmodulin. Gq-Gs cross-talk regulates collagen production in cardiac fibroblasts. J Biol Chem 278:24461–24468. doi:10.1074/jbc.M212659200

46.

Pandey KN (2010) Ligand-mediated endocytosis and intracellular sequestration of guanylyl cyclase/natriuretic peptide receptors: role of GDAY motif. Mol Cell Biochem 334:81–98. doi:10.1007/s11010-009-0332-x PubMedCrossRef

47.

Pilz RB, Casteel DE (2003) Regulation of gene expression by cyclic GMP. Circ Res 93:1034–1046. doi:10.1161/01.res.0000103311.52853.48 PubMedCrossRef

48.

Ponsioen B, Zhao J, Riedl J, Zwartkruis F, van der Krogt G, Zaccolo M, Moolenaar WH, Bos JL, Jalink K (2004) Detecting cAMP-induced Epac activation by fluorescence resonance energy transfer: Epac as a novel cAMP indicator. EMBO Rep 5:1176–1180. doi:10.1038/sj.embor.7400290 PubMedCrossRef

49.

Porter KE, Turner NA (2009) Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther 123:255–278. doi:10.1016/j.pharmthera.2009.05.002 PubMedCrossRef

50.

Rich TC, Xin W, Mehats C, Hassell KA, Piggott LA, Le X, Karpen JW, Conti M (2007) Cellular mechanisms underlying prostaglandin-induced transient cAMP signals near the plasma membrane of HEK-293 cells. Am J Physiol Cell Physiol 292:C319–C331. doi:10.1152/ajpcell.00121.2006 PubMedCrossRef

51.

Richter W, Xie M, Scheitrum C, Krall J, Movsesian MA, Conti M (2011) Conserved expression and functions of PDE4 in rodent and human heart. Basic Res Cardiol 106:249–262. doi:10.1007/s00395-010-0138-8 PubMedCrossRef

52.

Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA (2003) Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res 93:280–291. doi:10.1161/01.RES.0000087541.15600.2B PubMedCrossRef

53.

Sassi Y, Lipskaia L, Vandecasteele G, Nikolaev VO, Hatem SN, Cohen Aubart F, Russel FG, Mougenot N, Vrignaud C, Lechat P, Lompre AM, Hulot JS (2008) Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation. J Clin Invest 118:2747–2757. doi:10.1172/JCI35067 PubMedCrossRef

54.

Shishido T, Woo CH, Ding B, McClain C, Molina CA, Yan C, Yang J, Abe J (2008) Effects of MEK5/ERK5 association on small ubiquitin-related modification of ERK5: implications for diabetic ventricular dysfunction after myocardial infarction. Circ Res 102:1416–1425. doi:10.1161/circresaha.107.168138 PubMedCrossRef

55.

Snyder PB, Florio VA, Ferguson K, Loughney K (1999) Isolation, expression and analysis of splice variants of a human Ca2 +/calmodulin-stimulated phosphodiesterase (PDE1A). Cell Signal 11:535–544 (S0898-6568(99)00027-3[pii])PubMedCrossRef

56.

Sonnenburg WK, Seger D, Beavo JA (1993) Molecular cloning of a cDNA encoding the “61-kDa” calmodulin-stimulated cyclic nucleotide phosphodiesterase. Tissue-specific expression of structurally related isoforms. J Biol Chem 268:645–652PubMed

57.

Swaney JS, Roth DM, Olson ER, Naugle JE, Meszaros JG, Insel PA (2005) Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase. Proc Natl Acad Sci USA 102:437–442. doi:10.1073/pnas.0408704102 PubMedCrossRef

58.

Takizawa T, Gu M, Chobanian AV, Brecher P (1997) Effect of nitric oxide on DNA replication induced by angiotensin II in rat cardiac fibroblasts. Hypertension 30:1035–1040PubMed

59.

Terrin A, Di Benedetto G, Pertegato V, Cheung YF, Baillie G, Lynch MJ, Elvassore N, Prinz A, Herberg FW, Houslay MD, Zaccolo M (2006) PGE(1) stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: role of compartmentalized phosphodiesterases. J Cell Biol 175:441–451. doi:10.1083/jcb.200605050 PubMedCrossRef

60.

Tiede K, Melchior-Becker A, Fischer JW (2010) Transcriptional and posttranscriptional regulators of biglycan in cardiac fibroblasts. Basic Res Cardiol 105:99–108. doi:10.1007/s00395-009-0049-8 PubMedCrossRef

61.

Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3:349–363. doi:10.1038/nrm809 PubMedCrossRef

62.

Tsai EJ, Kass DA (2009) Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics. Pharmacol Ther 122:216–238. doi:10.1016/j.pharmthera.2009.02.009 PubMedCrossRef

63.

van den Borne SW, Diez J, Blankesteijn WM, Verjans J, Hofstra L, Narula J (2010) Myocardial remodeling after infarction: the role of myofibroblasts. Nat Rev Cardiol 7:30–37. doi:10.1038/nrcardio.2009.199 PubMedCrossRef

64.

Villarreal F, Epperson SA, Ramirez-Sanchez I, Yamazaki KG, Brunton LL (2009) Regulation of cardiac fibroblast collagen synthesis by adenosine: roles for Epac and PI3 K. Am J Physiol Cell Physiol 296:C1178–C1184. doi:10.1152/ajpcell.00291.2008 PubMedCrossRef

65.

von Hayn K, Werthmann RC, Nikolaev VO, Hommers LG, Lohse MJ, Bunemann M (2010) Gq-mediated Ca²⁺ signals inhibit adenylyl cyclases 5/6 in vascular smooth muscle cells. Am J Physiol Cell Physiol 298:C324–C332. doi:10.1152/ajpcell.00197.2009 CrossRef

66.

Willems IE, Havenith MG, De Mey JG, Daemen MJ (1994) The alpha-smooth muscle actin-positive cells in healing human myocardial scars. Am J Pathol 145:868–875PubMed

67.

Wu M, Melichian DS, de la Garza M, Gruner K, Bhattacharyya S, Barr L, Nair A, Shahrara S, Sporn PH, Mustoe TA, Tourtellotte WG, Varga J (2009) Essential roles for early growth response transcription factor Egr-1 in tissue fibrosis and wound healing. Am J Pathol 175:1041–1055. doi:10.2353/ajpath.2009.090241 PubMedCrossRef

68.

Yan C, Kim D, Aizawa T, Berk BC (2003) Functional interplay between angiotensin II and nitric oxide: cyclic GMP as a key mediator. Arterioscler Thromb Vasc Biol 23:26–36PubMedCrossRef

69.

Yokoyama U, Patel HH, Lai NC, Aroonsakool N, Roth DM, Insel PA (2008) The cyclic AMP effector Epac integrates pro- and anti-fibrotic signals. Proc Natl Acad Sci USA 105:6386–6391. doi:10.1073/pnas.0801490105 PubMedCrossRef

70.

Zaccolo M (2009) cAMP signal transduction in the heart: understanding spatial control for the development of novel therapeutic strategies. Br J Pharmacol 158:50–60. doi:10.1111/j.1476-5381.2009.00185.x PubMedCrossRef

71.

Zaccolo M, Pozzan T (2002) Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science 295:1711–1715. doi:10.1126/science.1069982 PubMedCrossRef

72.

Zhou HY, Chen WD, Zhu DL, Wu LY, Zhang J, Han WQ, Li JD, Yan C, Gao PJ (2010) The PDE1A-PKCalpha signaling pathway is involved in the upregulation of alpha-smooth muscle actin by TGF-beta1 in adventitial fibroblasts. J Vasc Res 47:9–15. doi:10.1159/000231716 PubMedCrossRef

Title: Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart
Authors: Clint L. Miller
Yujun Cai
Masayoshi Oikawa
Tamlyn Thomas
Wolfgang R. Dostmann
Manuela Zaccolo
Keigi Fujiwara
Chen Yan
Publication date: 01-11-2011
Publisher: Springer-Verlag
Published in: Basic Research in Cardiology / Issue 6/2011
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-011-0228-2

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