Circulation Research. 2002;91:1103-1113
doi: 10.1161/01.RES.0000046452.67724.B8
doi: 10.1161/01.RES.0000046452.67724.B8
© 2002 American Heart Association, Inc.
Reviews |
Gene Expression in Fibroblasts and Fibrosis
Involvement in Cardiac Hypertrophy
From the Departments of Cardiovascular Medicine (I.M., T.S., R.N.) and Clinical Bioinformatics (I.M., R.N.), University of Tokyo, Tokyo, Japan.
Correspondence to Ichiro Manabe, MD, PhD, Department of Cardiovascular Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan. E-mail manabe-tky{at}umin.ac.jp
Structural remodeling of the ventricular wall is a key determinant of clinical outcome in heart disease. Such remodeling involves the production and destruction of extracellular matrix proteins, cell proliferation and migration, and apoptotic and necrotic cell death. Cardiac fibroblasts are crucially involved in these processes, producing growth factors and cytokines that act as autocrine and paracrine factors, as well as extracellular matrix proteins and proteinases. Recent studies have shown that the interactions between cardiac fibroblasts and cardiomyocytes are essential for the progression of cardiac remodeling. This review addresses the functional role played by cardiac fibroblasts and the molecular mechanisms that govern their activity during cardiac hypertrophy and remodeling. A particular focus is the recent progress toward our understanding of the transcriptional regulatory mechanisms involved.
Key Words: transcription • fibrosis • myofibroblast • cardiac remodeling
This article has been cited by other articles:
 |
|
 |
|
  N. Sawada, H. Itoh, K. Miyashita, H. Tsujimoto, M. Sone, K. Yamahara, Z. P. Arany, F. Hofmann, and K. Nakao Cyclic GMP Kinase and RhoA Ser188 Phosphorylation Integrate Pro- and Antifibrotic Signals in Blood Vessels Mol. Cell. Biol., November 15, 2009; 29(22): 6018 - 6032. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Li, T. Ichikawa, L. Villacorta, J. S. Janicki, G. L. Brower, M. Yamamoto, and T. Cui Nrf2 Protects Against Maladaptive Cardiac Responses to Hemodynamic Stress Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1843 - 1850. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Banerjee, J. W. Fuseler, A. R. Intwala, and T. A. Baudino IL-6 loss causes ventricular dysfunction, fibrosis, reduced capillary density, and dramatically alters the cell populations of the developing and adult heart Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1694 - H1704. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. T. Weber, W. B. Weglicki, and R. U. Simpson Macro- and micronutrient dyshomeostasis in the adverse structural remodelling of myocardium Cardiovasc Res, February 15, 2009; 81(3): 500 - 508. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. U. Rehman, T. Mueller, and J. L. Januzzi Jr Characteristics of the Novel Interleukin Family Biomarker ST2 in Patients With Acute Heart Failure J. Am. Coll. Cardiol., October 28, 2008; 52(18): 1458 - 1465. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Cihakova, J. G. Barin, M. Afanasyeva, M. Kimura, D. Fairweather, M. Berg, M. V. Talor, G. C. Baldeviano, S. Frisancho, K. Gabrielson, et al. Interleukin-13 Protects Against Experimental Autoimmune Myocarditis by Regulating Macrophage Differentiation Am. J. Pathol., May 1, 2008; 172(5): 1195 - 1208. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pokreisz, G. Marsboom, and S. Janssens Pressure overload-induced right ventricular dysfunction and remodelling in experimental pulmonary hypertension: the right heart revisited Eur. Heart J. Suppl., December 1, 2007; 9(suppl_H): H75 - H84. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Fahrenbach, R. Mejia-Alvarez, and K. Banach The relevance of non-excitable cells for cardiac pacemaker function J. Physiol., December 1, 2007; 585(2): 565 - 578. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J.A. Frost and S. Engelhardt A Secretion Trap Screen in Yeast Identifies Protease Inhibitor 16 as a Novel Antihypertrophic Protein Secreted From the Heart Circulation, October 16, 2007; 116(16): 1768 - 1775. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. Spruill, A. S. Lowry, R. E. Stroud, C. E. Squires, I. M. Mains, E. C. Flack, C. Beck, J. S. Ikonomidis, A. J. Crumbley, P. J. McDermott, et al. Membrane-type-1 matrix metalloproteinase transcription and translation in myocardial fibroblasts from patients with normal left ventricular function and from patients with cardiomyopathy Am J Physiol Cell Physiol, October 1, 2007; 293(4): C1362 - C1373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Banerjee, J. W. Fuseler, R. L. Price, T. K. Borg, and T. A. Baudino Determination of cell types and numbers during cardiac development in the neonatal and adult rat and mouse Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1883 - H1891. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K Parker and D. E Ingber Extracellular matrix, mechanotransduction and structural hierarchies in heart tissue engineering Phil Trans R Soc B, August 29, 2007; 362(1484): 1267 - 1279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Nishida, N. Onohara, Y. Sato, R. Suda, M. Ogushi, S. Tanabe, R. Inoue, Y. Mori, and H. Kurose G{alpha}12/13-mediated Up-regulation of TRPC6 Negatively Regulates Endothelin-1-induced Cardiac Myofibroblast Formation and Collagen Synthesis through Nuclear Factor of Activated T Cells Activation J. Biol. Chem., August 10, 2007; 282(32): 23117 - 23128. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. H. Kumbar, A. VanBergen, C. Ocampo, S. Muangmingsuk, A. J. Griffin, and M. Gupta Adapter molecule DOC-2 is differentially expressed in pressure and volume overload hypertrophy and inhibits collagen synthesis in cardiac fibroblasts J Appl Physiol, May 1, 2007; 102(5): 2024 - 2032. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Koitabashi, M. Arai, S. Kogure, K. Niwano, A. Watanabe, Y. Aoki, T. Maeno, T. Nishida, S. Kubota, M. Takigawa, et al. Increased Connective Tissue Growth Factor Relative to Brain Natriuretic Peptide as a Determinant of Myocardial Fibrosis Hypertension, May 1, 2007; 49(5): 1120 - 1127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-l. Moore, S.-l. Tan, C.-y. Lo, L. Fang, Y.-D. Su, X.-M. Gao, E. A. Woodcock, R. J. Summers, G. W. Tregear, R. A. D. Bathgate, et al. Relaxin Antagonizes Hypertrophy and Apoptosis in Neonatal Rat Cardiomyocytes Endocrinology, April 1, 2007; 148(4): 1582 - 1589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. I. Jugdutt and C. Butler Ventricular Unloading, Tissue Angiotensin II, Matrix Modulation, and Function During Left Ventricular Assist Device Support J. Am. Coll. Cardiol., March 20, 2007; 49(11): 1175 - 1177. [Full Text] [PDF]
|
|
|
|
 |
|
 L. J Ellmers, N. J A Scott, J. Piuhola, N. Maeda, O. Smithies, C. M Frampton, A M. Richards, and V. A Cameron Npr1-regulated gene pathways contributing to cardiac hypertrophy and fibrosis J. Mol. Endocrinol., February 1, 2007; 38(2): 245 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Liu, S. Q. Sun, A. Hassid, and R. S. Ostrom cAMP Inhibits Transforming Growth Factor-beta-Stimulated Collagen Synthesis via Inhibition of Extracellular Signal-Regulated Kinase 1/2 and Smad Signaling in Cardiac Fibroblasts Mol. Pharmacol., December 1, 2006; 70(6): 1992 - 2003. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Goser, M. Andrassy, S. J. Buss, F. Leuschner, C. H. Volz, R. Ottl;, S. Zittrich;, N. Blaudeck, S. E. Hardt, G. Pfitzer, et al. Cardiac Troponin I but Not Cardiac Troponin T Induces Severe Autoimmune Inflammation in the Myocardium Circulation, October 17, 2006; 114(16): 1693 - 1702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Podgorska, K. Kocbuch, M. Grden, A. Szutowicz, and T. Pawelczyk Reduced ability to release adenosine by diabetic rat cardiac fibroblasts due to altered expression of nucleoside transporters J. Physiol., October 1, 2006; 576(1): 179 - 189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. Baudino, W. Carver, W. Giles, and T. K. Borg Cardiac fibroblasts: friend or foe? Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1015 - H1026. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Kapoun, N. J. Gaspar, Y. Wang, D. Damm, Y.-W. Liu, G. O'Young, D. Quon, A. Lam, K. Munson, T.-T. Tran, et al. Transforming Growth Factor-beta Receptor Type 1 (TGFbetaRI) Kinase Activity but Not p38 Activation Is Required for TGFbetaRI-Induced Myofibroblast Differentiation and Profibrotic Gene Expression Mol. Pharmacol., August 1, 2006; 70(2): 518 - 531. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Milting, A. Kassner, L. Arusoglu, H. E. Meyer, M. Morshuis, R. Brendel, B. Klauke, A. El Banayosy, and R. Korfer Influence of ACE-inhibition and mechanical unloading on the regulation of extracellular matrix proteins in the myocardium of heart transplantation candidates bridged by ventricular assist devices Eur J Heart Fail, May 1, 2006; 8(3): 278 - 283. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Miragoli, G. Gaudesius, and S. Rohr Electrotonic Modulation of Cardiac Impulse Conduction by Myofibroblasts Circ. Res., March 31, 2006; 98(6): 801 - 810. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Fairweather, S. Frisancho-Kiss, D. B. Njoku, J. F. Nyland, Z. Kaya, S. A. Yusung, S. E. Davis, J. A. Frisancho, M. A. Barrett, and N. R. Rose Complement Receptor 1 and 2 Deficiency Increases Coxsackievirus B3-Induced Myocarditis, Dilated Cardiomyopathy, and Heart Failure by Increasing Macrophages, IL-1beta, and Immune Complex Deposition in the Heart J. Immunol., March 15, 2006; 176(6): 3516 - 3524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Liu, A. S. Pachori, C. A. Ward, J. P. Davis, M. Gnecchi, D. Kong, L. Zhang, J. Murduck, S.-F. Yet, M. A. Perrella, et al. Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function FASEB J, February 1, 2006; 20(2): 207 - 216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Shigeyama, Y. Yasumura, A. Sakamoto, Y. Ishida, T. Fukutomi, M. Itoh, K. Miyatake, and M. Kitakaze Increased gene expression of collagen Types I and III is inhibited by {beta}-receptor blockade in patients with dilated cardiomyopathy Eur. Heart J., December 2, 2005; 26(24): 2698 - 2705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Iwata, R. T. Cowling, D. Gurantz, C. Moore, S. Zhang, J. X.-J. Yuan, and B. H. Greenberg Angiotensin-(1-7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2356 - H2363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ponten, E. Bergsten Folestad, K. Pietras, and U. Eriksson Platelet-Derived Growth Factor D Induces Cardiac Fibrosis and Proliferation of Vascular Smooth Muscle Cells in Heart-Specific Transgenic Mice Circ. Res., November 11, 2005; 97(10): 1036 - 1045. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Yu, R. R. Watson, J. J. Marchalonis, and D. F. Larson A role for T lymphocytes in mediating cardiac diastolic function Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H643 - H651. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Menon, M. Singh, and K. Singh Matrix metalloproteinases mediate {beta}-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes Am J Physiol Cell Physiol, July 1, 2005; 289(1): C168 - C176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Fujii, N. Onohara, Y. Maruyama, S. Tanabe, H. Kobayashi, M. Fukutomi, Y. Nagamatsu, N. Nishihara, R. Inoue, H. Sumimoto, et al. G{alpha}12/13-mediated Production of Reactive Oxygen Species Is Critical for Angiotensin Receptor-induced NFAT Activation in Cardiac Fibroblasts J. Biol. Chem., June 17, 2005; 280(24): 23041 - 23047. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Miyauchi, Z. Qu, Y. Miyauchi, S.-M. Zhou, H. Pak, W. J. Mandel, M. C. Fishbein, P.-S. Chen, and H. S. Karagueuzian Chronic nicotine in hearts with healed ventricular myocardial infarction promotes atrial flutter that resembles typical human atrial flutter Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2878 - H2886. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Vellaichamy, M. L. Khurana, J. Fink, and K. N. Pandey Involvement of the NF-{kappa}B/Matrix Metalloproteinase Pathway in Cardiac Fibrosis of Mice Lacking Guanylyl Cyclase/Natriuretic Peptide Receptor A J. Biol. Chem., May 13, 2005; 280(19): 19230 - 19242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Allessie, U. Schotten, S. Verheule, and E. Harks Gene Therapy for Repair of Cardiac Fibrosis: A Long Way to Tipperary Circulation, February 1, 2005; 111(4): 391 - 393. [Full Text] [PDF]
|
|
|
|
 |
|
 R. K. Dubey, E. K. Jackson, D. G. Gillespie, M. Rosselli, F. Barchiesi, A. Krust, H. Keller, L. C. Zacharia, and B. Imthurn Cytochromes 1A1/1B1- and Catechol-O-Methyltransferase-Derived Metabolites Mediate Estradiol-Induced Antimitogenesis in Human Cardiac Fibroblast J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 247 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Rothenberg, V. P. Nikolski, M. Watanabe, and I. R. Efimov Electrophysiology and anatomy of embryonic rabbit hearts before and after septation Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H344 - H351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Fairweather, S. Frisancho-Kiss, S. A. Yusung, M. A. Barrett, S. E. Davis, S. J.L. Gatewood, D. B. Njoku, and N. R. Rose Interferon-{gamma} Protects against Chronic Viral Myocarditis by Reducing Mast Cell Degranulation, Fibrosis, and the Profibrotic Cytokines Transforming Growth Factor-{beta}1, Interleukin-1{beta}, and Interleukin-4 in the Heart Am. J. Pathol., December 1, 2004; 165(6): 1883 - 1894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Franco, Y.-F. Chen, S. Oparil, J. A. Feng, D. Wang, F. Hage, and G. Perry Atrial Natriuretic Peptide Dose-Dependently Inhibits Pressure Overload-Induced Cardiac Remodeling Hypertension, November 1, 2004; 44(5): 746 - 750. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Polyakova, S. Hein, S. Kostin, T. Ziegelhoeffer, and J. Schaper Matrix metalloproteinases and their tissue inhibitors in pressure-overloaded human myocardium during heart failure progression J. Am. Coll. Cardiol., October 19, 2004; 44(8): 1609 - 1618. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Schroen, S. Heymans, U. Sharma, W. M. Blankesteijn, S. Pokharel, J. P.M. Cleutjens, J. G. Porter, C. T.A. Evelo, R. Duisters, R. E.W. van Leeuwen, et al. Thrombospondin-2 Is Essential for Myocardial Matrix Integrity: Increased Expression Identifies Failure-Prone Cardiac Hypertrophy Circ. Res., September 3, 2004; 95(5): 515 - 522. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Selvetella, E. Hirsch, A. Notte, G. Tarone, and G. Lembo Adaptive and maladaptive hypertrophic pathways: points of convergence and divergence Cardiovasc Res, August 15, 2004; 63(3): 373 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rosenkranz TGF-{beta}1 and angiotensin networking in cardiac remodeling Cardiovasc Res, August 15, 2004; 63(3): 423 - 432. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Stawowy, C. Margeta, H. Kallisch, N. G Seidah, M. Chretien, E. Fleck, and K. Graf Regulation of matrix metalloproteinase MT1-MMP/MMP-2 in cardiac fibroblasts by TGF-{beta}1 involves furin-convertase Cardiovasc Res, July 1, 2004; 63(1): 87 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tokudome, T. Horio, M. Fukunaga, H. Okumura, J. Hino, K. Mori, F. Yoshihara, S.-I. Suga, Y. Kawano, M. Kohno, et al. Ventricular Nonmyocytes Inhibit Doxorubicin-Induced Myocyte Apoptosis: Involvement of Endogenous Endothelin-1 as a Paracrine Factor Endocrinology, May 1, 2004; 145(5): 2458 - 2466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rohr Role of gap junctions in the propagation of the cardiac action potential Cardiovasc Res, May 1, 2004; 62(2): 309 - 322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Rudy Conductive Bridges in Cardiac Tissue: A Beneficial Role or an Arrhythmogenic Substrate? Circ. Res., April 2, 2004; 94(6): 709 - 711. [Full Text] [PDF]
|
|
|
|
|
|
M. C. LaPointe, M. Mendez, A. Leung, Z. Tao, and X.-P. Yang Inhibition of cyclooxygenase-2 improves cardiac function after myocardial infarction in the mouse Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1416 - H1424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Kapoun, F. Liang, G. O'Young, D. L. Damm, D. Quon, R. T. White, K. Munson, A. Lam, G. F. Schreiner, and A. A. Protter B-Type Natriuretic Peptide Exerts Broad Functional Opposition to Transforming Growth Factor-{beta} in Primary Human Cardiac Fibroblasts: Fibrosis, Myofibroblast Conversion, Proliferation, and Inflammation Circ. Res., March 5, 2004; 94(4): 453 - 461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Ocaranza, G. Diaz-Araya, J. E. Carreno, D. Munoz, J. P. Riveros, J. E. Jalil, and S. Lavandero Polymorphism in gene coding for ACE determines different development of myocardial fibrosis in rats Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H498 - H506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Shishido, N. Nozaki, S. Yamaguchi, Y. Shibata, J. Nitobe, T. Miyamoto, H. Takahashi, T. Arimoto, K. Maeda, M. Yamakawa, et al. Toll-Like Receptor-2 Modulates Ventricular Remodeling After Myocardial Infarction Circulation, December 9, 2003; 108(23): 2905 - 2910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Gaudesius, M. Miragoli, S. P. Thomas, and S. Rohr Coupling of Cardiac Electrical Activity Over Extended Distances by Fibroblasts of Cardiac Origin Circ. Res., September 5, 2003; 93(5): 421 - 428. [Abstract] [Full Text] [PDF]
|
|