Circulation Research. 2004;94:453-461
Published online before print January 15, 2004, doi: 10.1161/01.RES.0000117070.86556.9F
Published online before print January 15, 2004, doi: 10.1161/01.RES.0000117070.86556.9F
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2004 American Heart Association, Inc.
Molecular Medicine |
B-Type Natriuretic Peptide Exerts Broad Functional Opposition to Transforming Growth Factor-ß in Primary Human Cardiac Fibroblasts
Fibrosis, Myofibroblast Conversion, Proliferation, and Inflammation
From Scios Inc, Fremont, Calif.
Correspondence to Andrew A. Protter, Scios Inc, 6500 Paseo Padre Pkwy, Fremont, CA 94555. E-mail protter{at}sciosinc.com
The natriuretic peptides, including human B-type natriuretic peptide (BNP), have been implicated in the regulation of cardiac remodeling. Because transforming growth factor-ß (TGF-ß) is associated with profibrotic processes in heart failure, we tested whether BNP could inhibit TGF-ß–induced effects on primary human cardiac fibroblasts. BNP inhibited TGF-ß–induced cell proliferation as well as the production of collagen 1 and fibronectin proteins as measured by Western blot analysis. cDNA microarray analysis was performed on RNA from cardiac fibroblasts incubated in the presence or absence of TGF-ß and BNP for 24 and 48 hours. TGF-ß, but not BNP, treatment resulted in a significant change in the RNA profile. BNP treatment resulted in a remarkable reduction in TGF-ß effects; 88% and 85% of all TGF-ß–regulated mRNAs were affected at 24 and 48 hours, respectively. BNP opposed TGF-ß–regulated genes related to fibrosis (collagen 1, fibronectin, CTGF, PAI-1, and TIMP3), myofibroblast conversion (
-smooth muscle actin 2 and nonmuscle myosin heavy chain), proliferation (PDGFA, IGF1, FGF18, and IGFBP10), and inflammation (COX2, IL6, TNF-induced protein 6, and TNF superfamily, member 4). Lastly, BNP stimulated the extracellular signal-related kinase pathway via cyclic guanosine monophosphate–dependent protein kinase signaling, and two mitogen-activated protein kinase kinase inhibitors, U0126 and PD98059, reversed BNP inhibition of TGF-ß–induced collagen-1 expression. These findings demonstrate that BNP has a direct effect on cardiac fibroblasts to inhibit fibrotic responses via extracellular signal-related kinase signaling, suggesting that BNP functions as an antifibrotic factor in the heart to prevent cardiac remodeling in pathological conditions.
Key Words: B-type natriuretic peptide • transforming growth factor-ß • cardiac fibroblasts • fibrosis
This article has been cited by other articles:
 |
|
 |
|
  L. Zhou, A. N. Nguyen, D. Sohal, J. Ying Ma, P. Pahanish, K. Gundabolu, J. Hayman, A. Chubak, Y. Mo, T. D. Bhagat, et al. Inhibition of the TGF-{beta} receptor I kinase promotes hematopoiesis in MDS Blood, October 15, 2008; 112(8): 3434 - 3443. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. van Rooij, L. B. Sutherland, J. E. Thatcher, J. M. DiMaio, R. H. Naseem, W. S. Marshall, J. A. Hill, and E. N. Olson Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis PNAS, September 2, 2008; 105(35): 13027 - 13032. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Della Corte, G. Salerno, E. Chiosi, D. Iarussi, G. Santarpino, M. Miraglia, S. Naviglio, and M. De Feo Preoperative, postoperative and 1-year follow-up N-terminal pro-B-type natriuretic peptide levels in severe chronic aortic regurgitation: correlations with echocardiographic findings Interactive CardioVascular and Thoracic Surgery, June 1, 2008; 7(3): 419 - 424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. W Yip B-type natriuretic peptide: a treatment, not a diagnostic marker Heart, May 1, 2008; 94(5): 542 - 544. [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Rose and W. R. Giles Natriuretic peptide C receptor signalling in the heart and vasculature J. Physiol., January 15, 2008; 586(2): 353 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Li, Y. Zhang, J. Ying Ma, A. M. Kapoun, Q. Shao, I. Kerr, A. Lam, G. O'Young, F. Sannajust, P. Stathis, et al. Recombinant Vascular Endothelial Growth Factor 121 Attenuates Hypertension and Improves Kidney Damage in a Rat Model of Preeclampsia Hypertension, October 1, 2007; 50(4): 686 - 692. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Chen, T. J. Desai, J. Qian, K. Niederreither, J. Lu, and W. V. Cardoso Inhibition of Tgf{beta} signaling by endogenous retinoic acid is essential for primary lung bud induction Development, August 15, 2007; 134(16): 2969 - 2979. [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]
|
|
|
|
|
|
R. A. Rose, N. Hatano, S. Ohya, Y. Imaizumi, and W. R. Giles C-type natriuretic peptide activates a non-selective cation current in acutely isolated rat cardiac fibroblasts via natriuretic peptide C receptor-mediated signalling J. Physiol., April 1, 2007; 580(1): 255 - 274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Herrmann, S. Muller, I. Kindermann, L. Gunther, J. Konig, M. Bohm, and W. Herrmann Plasma B vitamins and their relation to the severity of chronic heart failure Am. J. Clinical Nutrition, January 1, 2007; 85(1): 117 - 123. [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]
|
|
|
|
|
|
Y. Luo, C. Jiang, A. J. Belanger, G. Y. Akita, S. C. Wadsworth, R. J. Gregory, and K. A. Vincent A Constitutively Active Hypoxia-Inducible Factor-1{alpha}/VP16 Hybrid Factor Activates Expression of the Human B-Type Natriuretic Peptide Gene Mol. Pharmacol., June 1, 2006; 69(6): 1953 - 1962. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-Y. Qian, A. Leung, P. Harding, and M. C. LaPointe PGE2 stimulates human brain natriuretic peptide expression via EP4 and p42/44 MAPK Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1740 - H1746. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Klinger, S. Thaker, J. Houtchens, I. R. Preston, N. S. Hill, and H. W. Farber Pulmonary hemodynamic responses to brain natriuretic Peptide and sildenafil in patients with pulmonary arterial hypertension. Chest, February 1, 2006; 129(2): 417 - 425. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. R. Potter, S. Abbey-Hosch, and D. M. Dickey Natriuretic Peptides, Their Receptors, and Cyclic Guanosine Monophosphate-Dependent Signaling Functions Endocr. Rev., February 1, 2006; 27(1): 47 - 72. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Nishikimi, N. Maeda, and H. Matsuoka The role of natriuretic peptides in cardioprotection Cardiovasc Res, February 1, 2006; 69(2): 318 - 328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Clerico, F. A. Recchia, C. Passino, and M. Emdin Cardiac endocrine function is an essential component of the homeostatic regulation network: physiological and clinical implications Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H17 - H29. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Saura, C. Zaragoza, B. Herranz, M. Griera, L. Diez-Marques, D. Rodriguez-Puyol, and M. Rodriguez-Puyol Nitric Oxide Regulates Transforming Growth Factor-{beta} Signaling in Endothelial Cells Circ. Res., November 25, 2005; 97(11): 1115 - 1123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Bouzeghrane, D. P. Reinhardt, T. L. Reudelhuber, and G. Thibault Enhanced expression of fibrillin-1, a constituent of the myocardial extracellular matrix in fibrosis Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H982 - H991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Patel, M. L. Valencik, A. M. Pritchett, J. C. Burnett Jr., J. A. McDonald, and M. M. Redfield Cardiac-specific attenuation of natriuretic peptide A receptor activity accentuates adverse cardiac remodeling and mortality in response to pressure overload Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H777 - H784. [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]
|
|
|
|
 |
|
 C. Freund, R. Schmidt-Ullrich, A. Baurand, S. Dunger, W. Schneider, P. Loser, A. El-Jamali, R. Dietz, C. Scheidereit, and M. W. Bergmann Requirement of Nuclear Factor-{kappa}B in Angiotensin II- and Isoproterenol-Induced Cardiac Hypertrophy In Vivo Circulation, May 10, 2005; 111(18): 2319 - 2325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Bonniaud, P. J. Margetts, M. Kolb, J. A. Schroeder, A. M. Kapoun, D. Damm, A. Murphy, S. Chakravarty, S. Dugar, L. Higgins, et al. Progressive Transforming Growth Factor {beta}1-induced Lung Fibrosis Is Blocked by an Orally Active ALK5 Kinase Inhibitor Am. J. Respir. Crit. Care Med., April 15, 2005; 171(8): 889 - 898. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Beffagna, G. Occhi, A. Nava, L. Vitiello, A. Ditadi, C. Basso, B. Bauce, G. Carraro, G. Thiene, J. A. Towbin, et al. Regulatory mutations in transforming growth factor-{beta}3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1 Cardiovasc Res, February 1, 2005; 65(2): 366 - 373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Swaney, D. M. Roth, E. R. Olson, J. E. Naugle, J. G. Meszaros, and P. A. Insel Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase PNAS, January 11, 2005; 102(2): 437 - 442. [Abstract] [Full Text] [PDF]
|
|