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(Circulation. 2005;111:2416-2417.)
© 2005 American Heart Association, Inc.

Editorial

Yin and Yang of Myocardial Transforming Growth Factor-ß₁

Timing Is Everything

Ronglih Liao, PhD

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

Top Introduction Essentials of TGF-ß... TGF-ß and Myocardial... TGF-ß and Myocardial... References

 
Ischemic heart disease is a leading cause of chronic myocardial failure and mortality in the United States.¹ After myocardial infarction (MI), the heart undergoes a well-characterized process of deleterious structural and molecular remodeling, marked by ventricular dilation, infarct wall thinning, and replacement fibrosis, with a corresponding progressive impairment of contractile function.² Recent work has suggested that supplementation of myocardial cells with exogenous bone marrow–derived stem cell populations may have the potential to regenerate lost cardiomyocytes and slow, or even reverse, the remodeling process.³ Although the importance of both postinjury myocardial remodeling and regeneration are well accepted, the critical mechanisms that underlie these processes remain unclear. As insight into the biology of myocardial injury and dysfunction increases, the role of stress-activated cytokines has achieved particular prominence.⁴ Two articles in this issue of Circulation highlight the importance of the stress-activated cytokine, transforming growth factor (TGF)-ß₁, in mediating the complex processes of cardiac remodeling and regeneration.

See pp 2430 and 2438

	Essentials of TGF-ß Signaling

Top Introduction Essentials of TGF-ß... TGF-ß and Myocardial... TGF-ß and Myocardial... References

 
First isolated >20 years ago, TGF-ß was identified from sarcoma cells based on its ability to potentiate the transforming and proliferative actions of epidermal growth factor on non-neoplastic fibroblasts.^5,6 Since then, the TGF-ß family has grown rapidly and at present consists of >30 structurally related members, including TGF-ß₁. This diverse cytokine superfamily has been subgrouped according to sequence similarity and specific downstream signaling pathways into the TGF-ß/activin/nodal family and the bone morphogenic protein/growth and differentiation factor/Muellerian inhibiting substance family.⁷ TGF-ß has been linked to a wide spectrum of biological processes, including cellular proliferation, growth, differentiation, and apoptosis.⁷ Within the cardiovascular system, TGF-ß₁ has been implicated in a variety of disorders. In response to myocardial stress, including both hemodynamic load⁸ and ischemia,⁹ cardiomyocytes generate and release TGF-ß₁. TGF-ß₁ signals via ligand-stimulated interactions of type I and II cellular receptors.¹⁰ These serine/theonine kinases subsequently phosphorylate pathway-restricted Smads (Smad 2/3), resulting in decreased affinity for inhibitor proteins and allowing oligomerization with Smad4. The resulting complex translocates to the cell nucleus and associates with both DNA binding cofactors and coactivators/corepressors, resulting in regulated transcription of target genes. TGF-ß may also signal through Smad-independent as well as transcription-independent mechanisms.

	TGF-ß and Myocardial Remodeling

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In this issue of Circulation, Okada and colleagues¹¹ further elucidate the importance of myocardial TGF-ß₁ signaling in post-MI ventricular remodeling. Using a mouse model of coronary ligation, the authors demonstrate that inhibition of circulating TGF-ß₁ through adenoviral-mediated overexpression of the soluble TGF-ß type II receptor (sTßRII) attenuated post-MI fibrosis and infarct wall thinning, as well as decreased ventricular chamber dilation and improved postinfarct contractile function and mortality. Although the inhibition of replacement fibrosis and the observed decrease in infarct dilation would seem paradoxical, the authors suggest that increased myofibroblast infiltration in the infarct region in animals treated with sTßRII prevented infarct expansion. The authors further suggest that the increase in infarct myofibroblasts was secondary to a relative reduction in posthealing apoptosis. Given the fluctuating adaptive and maladaptive nature of stress-activated cytokines in myocardial tissue,⁴ perhaps one of the most intriguing observations in this article is that of a "therapeutic window" for postinfarct TGF-ß₁ antagonism. Treatment with adenovirus expressing sTßRII 3 days postinfarct resulted in a beneficial remodeling response, whereas treatment initiated at 4 weeks was ineffective. Previous work expands on this window and suggests that antagonism of TGF-ß₁ at the time of MI may in fact be maladaptive both structurally and functionally.⁹ Such observations indicate that TGF-ß₁ may be protective at the time of myocardial ischemia, although deleterious soon thereafter because of acute remodeling. In addition, this work would suggest that TGF-ß₁ exerts little effect on chronic remodeling, in contrast to other myocardial stress-activated cytokines, notably tumor necrosis factor-.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

Top Introduction Essentials of TGF-ß... TGF-ß and Myocardial... TGF-ß and Myocardial... References

 
In addition to the remodeling of adult myocardium, numerous members of the TGF-ß superfamily also are essential to the process of cardiac development.¹² Moreover, TGF-ß members, including TGF-ß₁, mediate cardiomyogenic differentiation in embryonic stem cells, and have been found to be critical for the expression of cardiac-specific markers.^13,14 The article by Li and colleagues in this issue of Circulation¹⁵ furthers our understanding of the regulation of TGF-ß of cardiomyogenic differentiation and demonstrates the sufficiency of TGF-ß₁ in promoting cardiomyogenic differentiation in adult murine hematopoietic stem cells. The authors hypothesized that ex vivo predifferentiation of adult stem cells before myocardial implantation would improve the efficacy of this cell therapy modality. They found that treatment of CD117⁺ adult stem cells, isolated from murine bone marrow aspirates, were found to adopt a cardiac phenotype in vitro with TGF-ß₁ treatment, as marked by expression of the cardiac-specific transcription factors GATA4 and Nkx-2.5 and the subsequent expression of myofibril proteins. Pretreatment of adult hematopoietic stem cells for 24 hours with TGF-ß₁ also resulted in greater cardiomyogenic differentiation after intramyocardial injection of cells postinfarct. This was associated with enhanced contractile function by echocardiography and a reduction in postinfarct mortality at 3 months. Both survival of implanted cells and cell therapy–associated angiogenesis, however, were independent of TGF-ß₁ pretreatment.

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

 
Dr Liao is supported by funding from the National Institutes of Health grants HL-73756, HL-67297, and HL-71775.

	Footnotes

 
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction Essentials of TGF-ß... TGF-ß and Myocardial... TGF-ß and Myocardial... References

 

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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: 391–407.[CrossRef][Medline] [Order article via Infotrieve]
    
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