(Circulation. 2005;111:2416-2417.)
© 2005 American Heart Association, Inc.
Editorial |
From the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Mass.
Reprint requests to Dr Ronglih Liao, Cardiac Muscle Research Laboratory, Whitaker Cardiovascular Institute, Boston University School of Medicine, 650 Albany St, X-726, Boston, MA 02118. E-mail rliao{at}bu.edu
Key Words: Editorials myocardial infarction remodeling stem cells transforming growth factors
| Introduction |
|---|
|
|
|---|
See pp 2430 and 2438
| Essentials of TGF-ß Signaling |
|---|
|
|
|---|
| TGF-ß and Myocardial Remodeling |
|---|
|
|
|---|
.4 Although the mechanism(s) that mediate the widely divergent and temporally regulated response of injured myocardium to TGF-ß1 remains unclear, it may be hypothesized that the predominant cell type stimulated (ie, cardiomyocyte versus fibroblast), as well as the distinct downstream signaling cascades activated, likely play important roles. | TGF-ß and Myocardial Regeneration |
|---|
|
|
|---|
Interestingly, the marked effects of TGF-ß1 on adult stem cells after implantation required only a minimal 24-hour preimplantation treatment period, and as such, may help explain the previous results observed with TGF-ß1 antagonism postinfarct.9,11 Perhaps within the first 24 to 72 hours after cardiac injury, locally released TGF-ß1 may promote endogenous, albeit inadequate, regeneration via stimulation of endogenous adult stem cell populations. Such a mechanism would explain how inhibition of TGF-ß1 at the time of infarction is detrimental.9 After this hyperacute time period, the majority of stem cell homing and repair may be completed. As such, TGF-ß1 may not be required for differentiation of endogenous stem cells and may, at this stage, have detrimental effects, as suggested by Okada and associates.11
Conclusions and Perspectives
Both cardiac remodeling and regeneration represent exceedingly complicated and dynamic processes, an orchestra involving multiple cell types and stimulant factors, and highly regulated both temporally and spatially. The complex and sometimes paradoxical effects that a single factor, in this case TGF-ß1, can induce on these processes are well demonstrated in the articles by Okada et al11 and Li et al.15 These articles not only prove a causal relationship between TGF-ß1 and both structural remodeling and adult stem cell differentiation but also suggest a therapeutic potential for the use of either TGF-ß1 antagonists (in the case of remodeling) or agonists (in the case of stem cell differentiation). That said, there is still much that is left unknown. In particular, given the adaptive and maladaptive aspects of stress-activated cytokines, delineating the molecular signaling pathways that mediate each of the observed results is crucial if anticytokine or procytokine therapies are to become reality.
| Acknowledgments |
|---|
| Footnotes |
|---|
| References |
|---|
|
|
|---|
2. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation. 1990; 81: 11611172.
3. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Bone marrow cells regenerate infarcted myocardium. Nature. 2001; 410: 701705.[CrossRef][Medline] [Order article via Infotrieve]
4. Mann DL. Stress-activated cytokines and the heart: from adaptation to maladaptation. Annu Rev Physiol. 2003; 65: 81101.[CrossRef][Medline] [Order article via Infotrieve]
5. Roberts AB, Anzano MA, Lamb LC, Smith JM, Frolik CA, Marquardt H, Todaro GJ, Sporn MB. Isolation from murine sarcoma cells of novel transforming growth factors potentiated by EGF. Nature. 1982; 295: 417419.[CrossRef][Medline] [Order article via Infotrieve]
6. Massague J. Type beta transforming growth factor from feline sarcoma virus-transformed rat cells. Isolation and biological properties. J Biol Chem. 1984; 259: 97569761.
7. Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003; 113: 685700.[CrossRef][Medline] [Order article via Infotrieve]
8. Ruwhof C, van Wamel AE, Egas JM, van der Laarse A. Cyclic stretch induces the release of growth promoting factors from cultured neonatal cardiomyocytes and cardiac fibroblasts. Mol Cell Biochem. 2000; 208: 8998.[CrossRef][Medline] [Order article via Infotrieve]
9. Ikeuchi M, Tsutsui H, Shiomi T, Matsusaka H, Matsushima S, Wen J, Kubota T, Takeshita A. Inhibition of TGF-beta signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction. Cardiovasc Res. 2004; 64: 526535.
10. Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997; 390: 465471.[CrossRef][Medline] [Order article via Infotrieve]
11. Okada H, Takemura G, Kosai K-i, Li Y, Takahashi T, Esaki M, Yuge K, Miyata S, Maruyama R, Mikami A, Minatoguchi S, Fujiwara T, Fujiwara H. Postinfarction gene therapy against transforming growth factor-beta signal modulates infarct tissue dynamics and attenuates left ventricular remodeling and heart failure. Circulation. 2005; 111: 24302437.
12. Azhar M, Schultz Jel J, Grupp I, Dorn GW II, Meneton P, Molin DG, Gittenberger-de Groot AC, Doetschman T. Transforming growth factor beta in cardiovascular development and function. Cytokine Growth Factor Rev. 2003; 14: 391407.[CrossRef][Medline] [Order article via Infotrieve]
13. Sachinidis A, Fleischmann BK, Kolossov E, Wartenberg M, Sauer H, Hescheler J. Cardiac specific differentiation of mouse embryonic stem cells. Cardiovasc Res. 2003; 58: 278291.
14. Behfar A, Zingman LV, Hodgson DM, Rauzier JM, Kane GC, Terzic A, Puceat M. Stem cell differentiation requires a paracrine pathway in the heart. FASEB J. 2002; 16: 15581566.
15. Li T-S, Hayashi M, Ito H, Furutani A, Murata T, Matsuzaki M, Hamano K. Regeneration of infarcted myocardium by intramyocardial implantation of ex vivo transforming growth factor-betapreprogrammed bone marrow stem cells. Circulation. 2005; 111: 24382445.
Related Articles:
Circulation 2005 111: 2430-2437.
Circulation 2005 111: 2438-2445.
This article has been cited by other articles:
![]() |
M. Bujak and N. G. Frangogiannis The role of TGF-{beta} signaling in myocardial infarction and cardiac remodeling Cardiovasc Res, May 1, 2007; 74(2): 184 - 195. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. Hauck, C. Harms, D. Grothe, J. An, K. Gertz, G. Kronenberg, R. Dietz, M. Endres, and R. von Harsdorf Critical Role for FoxO3a-Dependent Regulation of p21CIP1/WAF1 in Response to Statin Signaling in Cardiac Myocytes Circ. Res., January 5, 2007; 100(1): 50 - 60. [Abstract] [Full Text] [PDF] |
||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 2005 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |