Published online before print June 24, 2004, doi: 10.1161/01.RES.0000136520.07995.aa
© 2004 American Heart Association, Inc.
Molecular Medicine |
Valvular Myofibroblast Activation by Transforming Growth Factor-ß
Implications for Pathological Extracellular Matrix Remodeling in Heart Valve Disease
From the Department of Molecular, Cellular, and Developmental Biology (G.A.W., L.A.L.) and the Department of Chemical Engineering and the Howard Hughes Medical Institute (K.S.M., D.N.S., K.S.A.), University of Colorado, Boulder.
Correspondence to Dr Leslie A. Leinwand, Department of Molecular, Cellular, and Developmental Biology, Campus Box 347, University of Colorado, Boulder, CO 80309. E-mail Leslie.Leinwand{at}colorado.edu
The pathogenesis of cardiac valve disease correlates with the emergence of muscle-like fibroblasts (myofibroblasts). These cells display prominent stress fibers containing 
-smooth muscle actin (-SMA) and are believed to differentiate from valvular interstitial cells (VICs). However, the biological factors that initiate myofibroblast differentiation and activation in valves remain unidentified. We show that transforming growth factor-ß1 (TGF-ß1) mediates differentiation of VICs into active myofibroblasts in vitro in a dose-dependent manner, as determined by a significant increase in -SMA and the dramatic augmentation of stress fiber formation and alignment. Additionally, TGF-ß1 and increased mechanical stress function synergistically to enhance contractility. In turn, contractile valve myofibroblasts exert tension on the extracellular matrix, resulting in a dramatic realignment of extracellular fibronectin fibrils. TGF-ß1 also inhibits valve myofibroblast proliferation without enhancing apoptosis. Our results are consistent with activation of a highly contractile myofibroblast phenotype by TGF-ß1 and are the first to connect valve myofibroblast contractility with pathological valve matrix remodeling. We suggest that the activation of contractile myofibroblasts by TGF-ß1 may be a significant first step in promoting alterations to the valve matrix architecture that are evident in valvular heart disease.
Key Words: valvular heart disease • valvular interstitial cells • myofibroblasts • TGF-ß1 • -smooth muscle actin • contractility
This article has been cited by other articles:
 |
|
 |
|
  M. C. Cushing, P. D. Mariner, J.-T. Liao, E. A. Sims, and K. S. Anseth Fibroblast growth factor represses Smad-mediated myofibroblast activation in aortic valvular interstitial cells FASEB J, June 1, 2008; 22(6): 1769 - 1777. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. G. Rasmussen, S. H. Poulsen, E. Dupont, K. Ostergaard, G. Safikhany, and H. Egeblad Ergotamine-derived dopamine agonists and left ventricular function in Parkinson patients: systolic and diastolic function studied by conventional echocardiography, tissue Doppler imaging, and two-dimensional speckle tracking Eur J Echocardiogr, May 7, 2008; (2008) jen160v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Pho, W. Lee, D. R. Watt, C. Laschinger, C. A. Simmons, and C. A. McCulloch Cofilin is a marker of myofibroblast differentiation in cells from porcine aortic cardiac valves Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1767 - H1778. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. B. Donnelly Cardiac Valvular Pathology: Comparative Pathology and Animal Models of Acquired Cardiac Valvular Diseases Toxicol Pathol, February 1, 2008; 36(2): 204 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Horan, S. Wood, V. Ona, D. J. Li, M. E. Lukashev, P. H. Weinreb, K. J. Simon, K. Hahm, N. E. Allaire, N. J. Rinaldi, et al. Partial Inhibition of Integrin {alpha}v 6 Prevents Pulmonary Fibrosis without Exacerbating Inflammation Am. J. Respir. Crit. Care Med., January 1, 2008; 177(1): 56 - 65. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Meng, L. Ao, Y. Song, A. Babu, X. Yang, M. Wang, M. J. Weyant, C. A. Dinarello, J. C. Cleveland Jr., and D. A. Fullerton Expression of functional Toll-like receptors 2 and 4 in human aortic valve interstitial cells: potential roles in aortic valve inflammation and stenosis Am J Physiol Cell Physiol, January 1, 2008; 294(1): C29 - C35. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Liu, V. R. Joag, and A. I. Gotlieb The Emerging Role of Valve Interstitial Cell Phenotypes in Regulating Heart Valve Pathobiology Am. J. Pathol., November 1, 2007; 171(5): 1407 - 1418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Simionescu, D. T. Simionescu, and N. R. Vyavahare Osteogenic Responses in Fibroblasts Activated by Elastin Degradation Products and Transforming Growth Factor-{beta}1: Role of Myofibroblasts in Vascular Calcification Am. J. Pathol., July 1, 2007; 171(1): 116 - 123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. A. LaFramboise, D. Scalise, P. Stoodley, S. R. Graner, R. D. Guthrie, J. A. Magovern, and M. J. Becich Cardiac fibroblasts influence cardiomyocyte phenotype in vitro Am J Physiol Cell Physiol, May 1, 2007; 292(5): C1799 - C1808. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Arishiro, M. Hoshiga, N. Negoro, D. Jin, S. Takai, M. Miyazaki, T. Ishihara, and T. Hanafusa Angiotensin Receptor-1 Blocker Inhibits Atherosclerotic Changes and Endothelial Disruption of the Aortic Valve in Hypercholesterolemic Rabbits J. Am. Coll. Cardiol., April 3, 2007; 49(13): 1482 - 1489. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. B. Hinton Jr, J. Lincoln, G. H. Deutsch, H. Osinska, P. B. Manning, D. W. Benson, and K. E. Yutzey Extracellular Matrix Remodeling and Organization in Developing and Diseased Aortic Valves Circ. Res., June 9, 2006; 98(11): 1431 - 1438. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Leask Invited commentary. Ann. Thorac. Surg., March 1, 2006; 81(3): 927 - 927. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Skowasch, S. Schrempf, N. Wernert, M. Steinmetz, A. Jabs, I. Tuleta, U. Welsch, C. J. Preusse, J. A. Likungu, A. Welz, et al. Cells of primarily extravalvular origin in degenerative aortic valves and bioprostheses Eur. Heart J., December 1, 2005; 26(23): 2576 - 2580. [Abstract] [Full Text] [PDF]
|
|