doi: 10.1161/CIRCULATIONAHA.107.735381
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(Circulation. 2007;116:2096-2098.)
© 2007 American Heart Association, Inc.
Editorial |
The Transforming Growth Factor-ß/Smad3 Pathway
Coming of Age as a Key Participant in Cardiac Remodeling
From the Division of Cardiology, Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Fla.
Correspondence to Dr Joshua M. Hare, MD, Chief, Division of Cardiology, Director, Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Clinical Research Building, Suite 1124, 1120 NW 14th St, Miami, FL 33136. E-mail jhare{at}med.miami.edu
Key Words: Editorials • inflammation • myocardial infarction • remodeling • Smad3 protein • transforming growth factor-ß
Myocardial infarction (MI) is followed by a well-described sequence of events known as postinfarction ventricular remodeling, a process that involves both the infarct scar itself and the residual surviving myocardium.1 The net results of infarct remodeling are changes in chamber size, function, and geometry. Furthermore, the remodeled ventricle becomes a substrate for both heart failure and sudden cardiac death. The elements of post-MI remodeling include infarct expansion, neurohormonal activation, myocardial hypertrophy, myocardial fibrosis, and cellular apoptosis.
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These are linked physiological responses that attempt to compensate for the sudden decrease in contractility resulting from acute myocardial cell death.2 Infarct expansion is the thinning of the infarcted segment from slippage and stretching of myocytes and cell rupture. It is highly influenced by hemodynamic loading conditions.3 The prototypic pathways that participate in post-MI remodeling include the autonomic nervous system and renin-angiotensin-aldosterone system, which may be an attempt to maintain blood pressure and cardiac output.4 Over time, however, elevated adrenergic activity may lead to further myocardial cell loss from apoptosis,5 and both adrenergic and renin-angiotensin-aldosterone system upregulation have an adverse impact on cardiac hemodynamics. Myocardial hypertrophy, fibrosis, and apoptosis are primarily seen in the noninfarcted regions of the heart, particularly within the peri-infarct zones.2,6–8 Hypertrophy occurs in response to the increased workload for the surviving myocardiocytes, especially under suboptimal hemodynamic conditions. Myocardial hypertrophy, fibrosis, and apoptosis in the noninfarcted regions are believed to result, in part, from the neurohormonal activation of the sympathetic nervous system, renin-angiotensin-aldosterone system and cytokine cascades. The effect of these processes is to further compound the myocardial damage sustained during the initial acute injury. The end result of these remodeling responses is global ventricular dilatation, which is a significant predictor of dysfunction and future mortality.9
Understanding the components of remodeling has led to advances in therapeutic strategies. Currently available medications have been used to counteract the compensatory mechanism of postinfarction ventricular remodeling and consequently reduce morbidity and mortality. In some instances, these strategies have improved left ventricular morphology and function.7,8,10 In the acute phase of an MI, significant emphasis is placed on timely revascularization to reduce infarct size. In the peri-MI and post-MI periods, treatment strategies are aimed at unloading the heart and circumventing neurohumoral activation. Medical regimens for MI management typically use 5 or more drugs to reduce mortality in the acute phase and to minimize adverse ventricular remodeling. Nitrates, angiotensin-converting enzyme inhibitors, and ß-blockers are used to reduce hemodynamic stress and infarct expansion and to preserve left ventricular morphology.11–15 Angiotensin-converting enzyme inhibitors and aldosterone antagonists are used to block the renin-angiotensin-aldosterone system to limit deleterious effects on hemodynamics and propagation of inflammation.15–17 Statins have pleiotropic actions of modulating inflammation and extracellular matrix metabolism, which may influence remodeling.18,19 However, these regimens do not fully address inflammation, which is a critical factor in postinfarction remodeling.
As the major driver of the infarct healing process, inflammation has a profound impact on postinfarction ventricular remodeling because remodeling and infarct healing are inextricably linked.20,21 Inflammation is triggered by cell necrosis in the infarction zone. Studies of humans and animal models have shown complement activation, generation of reactive oxygen species, and substantial cytokine release, which is then followed by the influx of inflammatory cells into the infarcted region within hours of an MI. The inflammatory response can cause further myocardial damage through direct cytotoxicity by neutrophils,22,23 as well as through the downstream effects of reactive oxygen species.24 However, it is also evident that the inflammatory response is absolutely necessary for infarct healing.20,21 Inflammatory cells are responsible for the clearance of necrotic cellular debris and disrupted extracellular matrix that is a prerequisite to the healing process. Inflammatory cells create the milieu required for migration, proliferation, and differentiation of myofibroblasts and endothelial cells necessary for extracellular matrix reconstruction, neovascularization, and ultimately scar formation. Therefore, the balance between the destructive and healing activities of the inflammatory response has a profound effect on the postinfarction remodeling process.
To date, modulating the inflammatory process in the peri-MI setting in order to minimize adverse ventricular remodeling has been difficult. Clearly, a broad inhibition of the inflammation has been shown to be harmful for MI patients.25 Recent clinical trials have shown that therapies targeted to specific portions of the inflammatory response are not necessarily harmful but also show no significant benefit in MI patients. These include an inhibitor of complement C5a,26,27 monoclonal antibodies that suppress neutrophil activity,28,29 and inhibitors of tumor necrosis factor-
.30 It is likely that the redundancy of inflammatory response processes may have contributed to the negative results of these trials. However, the crucial role of inflammation in infarct healing and the resulting ventricular remodeling make continued investigation of this area imperative.
In this issue of the journal, Bujak et al31 present a study that provides insights on the role of the transforming growth factor-ß (TGF-ß)/Smad3 pathway in cardiac remodeling. In the cardiovascular system, TGF-ß is implicated in the development and progression of hypertension, coronary artery restenosis, heart failure, and atherosclerosis.11,12 TGF-ß is a cytokine with a broad range of regulatory effects on inflammation, cell proliferation, and wound healing and it modulates these processes primarily via signaling pathway proteins called Smads, of which 8 are known in humans. In particular, the TGF-B/Smad3 pathway is of interest because of its regulatory effects on the inflammatory response. This pathway suppresses cytokine and chemokine expression in immune and endothelial cells and reduces neutrophil and macrophage chemotaxis. In the context of ventricular remodeling, another interesting aspect of the TGF-ß/Smad3 pathway is the regulation of fibroblast activity. In general, TGF-ß inhibits fibroblast proliferation. However, it induces phenotypic changes in fibroblasts to increase production of extracellular matrix proteins. Therefore, as suggested by Bujak et al,31 the TGF-ß/Smad3 pathway is a promising avenue through which the damaging effects of inflammation might be reduced without hampering beneficial infarct healing activities.
Using a Smad3-knockout mouse, these investigators31 studied the role of the TGF-ß/Smad3 pathway in postinfarction ventricular remodeling. Specifically, Smad3-null mice showed marked reductions in global ventricular dilatation and substantially less diastolic dysfunction relative to wild-type mice. Smad3-null mice also exhibit decreased neurohumoral activation with a reduction in the peak cytokine release.
Furthermore, the investigators have provided substantial clarity into the nuances of TGF-ß/Smad3 modulation of the sequence of events that contributes to infarct healing and ventricular remodeling. In an elegant fashion, they have been able to dissect out the portions of each of these pathways that are influenced by TGF-ß in a Smad3-dependent or -independent fashion. With such fine mapping of the regulatory roles with an understanding of the timing, it may be possible to devise a strategy for manipulating Smad3 activity at specific time points in the postinfarction period to allow the beneficial actions of TGF-ß to continue while suppressing the deleterious activities.
For example, the number of neutrophils in the infarct region of Smad3-null mice was markedly less than those of wild-type mice. Interestingly, the number of macrophages and the timing of inflammatory cell clearance were equivalent between the 2 genotypes, implying that neutrophil chemotaxis is Smad3-dependent whereas macrophage recruitment and inflammatory cell clearance are Smad3-independent. Therefore, appropriately timed suppression of Smad3 activity could limit the number of infiltrating neutrophils, thereby reducing myocardial damage without affecting the necessary macrophage activity.
In another example, total cytokine production in Smad3-null mice was reduced compared with that seen in wild-type mice. However, the timing of when cytokine production ceased in the infarct region was the same in Smad3-null and wild-type mice. These results would suggest that cytokine production is enhanced in a Smad3-dependent manner but that the timing of the suppression of cytokine production is independent of Smad3 activity. These findings would imply that the amplitude of the inflammatory response could be altered through manipulation of Smad3 activity.
Finally, collagen content within the infarct region of the Smad3-null mice was substantially less than in the wild-type mice, again implying that collagen deposition is a Smad3-dependent activity. The result of having lower collagen content within the infarct zone was less diastolic dysfunction, presumably because of a reduction in ventricular stiffness.
Each of these examples illustrates an advance in our understanding for the role of TGF-ß and Smad3 in the inflammatory response to an MI and postinfarction ventricular remodeling. The study clearly shows the potential for manipulating Smad3 activity to ameliorate adverse ventricular remodeling while maintaining the beneficial aspects of infarct healing. The temporal context for TGF-ß/Smad3 activity offers the possibility that Smad3 activity could be modulated at specific time points during infarct healing to maximize the beneficial effects while minimizing possible deleterious pleiotropic effects. Another interesting line of study would be to examine whether the early reduction in diastolic dysfunction through suppression of collagen deposition and the subsequent improvements in hemodynamic loading conditions will result in improved left ventricular function over time relative to wild-type mice.
Together, the findings presented in this work by Bujak et al31 have dissected out a specific pathophysiological role for TGF/SMAD as a key player in the inflammatory component of post-MI remodeling. By separating adverse from beneficial effects of inflammation in post-MI healing, the stage may be set for the development of novel therapeutic approaches for ventricular remodeling.
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Acknowledgments |
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Sources of Funding
The authors are supported by National Institutes of Health grants HL-65455, HL084275, AG025017, and U54HL081028 and American Heart Association Grant 0665420U.
Disclosures
None.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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