Basic Research in Cardiology

, Volume 106, Issue 6, pp 1023–1039 | Cite as

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

  • Clint L. Miller
  • Yujun Cai
  • Masayoshi Oikawa
  • Tamlyn Thomas
  • Wolfgang R. Dostmann
  • Manuela Zaccolo
  • Keigi Fujiwara
  • Chen YanEmail author
Original Contribution


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.


Cyclic nucleotide Phosphodiesterase Myofibroblast Cardiac fibrosis 



We thank Dr. Soyeon Lim, Dr. Nhat-Tu Le, and Dr. Yuichiro Takei (University of Rochester, USA) for providing cardiac fibroblasts. We thank Dr. Kees Jalink (The Netherlands Cancer Institute, The Netherlands) for providing the permission to use the Epac1-H30-cyto construct. We thank Dr. Rajesh Kukreja (Virginia Commonwealth University, USA) for providing Ad-PKG I shRNA. We thank Dr. Jian-Dong Li (University of Rochester, USA) for providing the Smad-binding element-luciferase reporter construct and plasmids encoding Smad2 and Smad3. This work was supported by an American Heart Association Established Investigator Award 0740021N (to C.Y.), NIH grants HL088400 and HL077789 (to C.Y.), American Heart Association Predoctoral Fellowship 0815730D (to C.L.M.), This work was also supported by NIH HL68891 (to W.R.D.) and the Totman Trust for Biomedical Research (to W.R.D.) and by the British Heart Foundation PG/07/091/23698 (to M.Z.).

Supplementary material

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Online Supplement 1 (PDF 4939 kb)


  1. 1.
    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 PubMedCrossRefGoogle Scholar
  2. 2.
    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 PubMedCrossRefGoogle Scholar
  3. 3.
    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 PubMedCrossRefGoogle Scholar
  4. 4.
    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 PubMedCrossRefGoogle Scholar
  5. 5.
    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 PubMedCrossRefGoogle Scholar
  6. 6.
    Beavo JA, Hardman JG, Sutherland EW (1970) Hydrolysis of cyclic guanosine and adenosine 3′, 5′-monophosphates by rat and bovine tissues. J Biol Chem 245:5649–5655PubMedGoogle Scholar
  7. 7.
    Berk BC, Fujiwara K, Lehoux S (2007) ECM remodeling in hypertensive heart disease. J Clin Invest 117:568–575. doi: 10.1172/JCI31044 PubMedCrossRefGoogle Scholar
  8. 8.
    Bode DC, Kanter JR, Brunton LL (1991) Cellular distribution of phosphodiesterase isoforms in rat cardiac tissue. Circ Res 68:1070–1079PubMedGoogle Scholar
  9. 9.
    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 PubMedCrossRefGoogle Scholar
  10. 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 116:3110–3116PubMedGoogle Scholar
  11. 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 PubMedCrossRefGoogle Scholar
  12. 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 PubMedCrossRefGoogle Scholar
  13. 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 PubMedGoogle Scholar
  14. 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 PubMedCrossRefGoogle Scholar
  15. 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 PubMedCrossRefGoogle Scholar
  16. 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 PubMedCrossRefGoogle Scholar
  17. 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 PubMedCrossRefGoogle Scholar
  18. 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 PubMedCrossRefGoogle Scholar
  19. 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 PubMedGoogle Scholar
  20. 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 PubMedCrossRefGoogle Scholar
  21. 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 PubMedCrossRefGoogle Scholar
  22. 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 272:26879–26886PubMedCrossRefGoogle Scholar
  23. 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 PubMedCrossRefGoogle Scholar
  24. 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 PubMedCrossRefGoogle Scholar
  25. 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 PubMedCrossRefGoogle Scholar
  26. 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 PubMedCrossRefGoogle Scholar
  27. 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 104:2338–2343PubMedCrossRefGoogle Scholar
  28. 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 PubMedCrossRefGoogle Scholar
  29. 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 PubMedCrossRefGoogle Scholar
  30. 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 PubMedCrossRefGoogle Scholar
  31. 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 PubMedCrossRefGoogle Scholar
  32. 32.
    Leask A, Abraham DJ (2004) TGF-beta signaling and the fibrotic response. FASEB J 18:816–827. doi: 10.1096/fj.03-1273rev PubMedCrossRefGoogle Scholar
  33. 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 PubMedCrossRefGoogle Scholar
  34. 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 PubMedCrossRefGoogle Scholar
  35. 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 PubMedCrossRefGoogle Scholar
  36. 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 PubMedCrossRefGoogle Scholar
  37. 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 PubMedCrossRefGoogle Scholar
  38. 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 PubMedCrossRefGoogle Scholar
  39. 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 PubMedCrossRefGoogle Scholar
  40. 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/ PubMedCrossRefGoogle Scholar
  41. 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 PubMedCrossRefGoogle Scholar
  42. 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 PubMedCrossRefGoogle Scholar
  43. 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 CrossRefGoogle Scholar
  44. 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 PubMedCrossRefGoogle Scholar
  45. 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 Google Scholar
  46. 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 PubMedCrossRefGoogle Scholar
  47. 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 PubMedCrossRefGoogle Scholar
  48. 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 PubMedCrossRefGoogle Scholar
  49. 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 PubMedCrossRefGoogle Scholar
  50. 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 PubMedCrossRefGoogle Scholar
  51. 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 PubMedCrossRefGoogle Scholar
  52. 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 PubMedCrossRefGoogle Scholar
  53. 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 PubMedCrossRefGoogle Scholar
  54. 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 PubMedCrossRefGoogle Scholar
  55. 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])PubMedCrossRefGoogle Scholar
  56. 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 268:645–652PubMedGoogle Scholar
  57. 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 PubMedCrossRefGoogle Scholar
  58. 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 30:1035–1040PubMedGoogle Scholar
  59. 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 PubMedCrossRefGoogle Scholar
  60. 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 PubMedCrossRefGoogle Scholar
  61. 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 PubMedCrossRefGoogle Scholar
  62. 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 PubMedCrossRefGoogle Scholar
  63. 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 PubMedCrossRefGoogle Scholar
  64. 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 PubMedCrossRefGoogle Scholar
  65. 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 CrossRefGoogle Scholar
  66. 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 145:868–875PubMedGoogle Scholar
  67. 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 PubMedCrossRefGoogle Scholar
  68. 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 23:26–36PubMedCrossRefGoogle Scholar
  69. 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 PubMedCrossRefGoogle Scholar
  70. 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 PubMedCrossRefGoogle Scholar
  71. 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 PubMedCrossRefGoogle Scholar
  72. 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 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Clint L. Miller
    • 1
  • Yujun Cai
    • 1
  • Masayoshi Oikawa
    • 1
  • Tamlyn Thomas
    • 1
  • Wolfgang R. Dostmann
    • 2
  • Manuela Zaccolo
    • 3
  • Keigi Fujiwara
    • 1
  • Chen Yan
    • 1
    Email author
  1. 1.Department of Pharmacology and Physiology, Department of Medicine, Aab Cardiovascular Research InstituteUniversity of Rochester School of Medicine and DentistryRochesterUSA
  2. 2.Department of PharmacologyUniversity of Vermont College of MedicineBurlingtonUSA
  3. 3.Institute of Neuroscience and PsychologyUniversity of GlasgowGlasgowUK

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