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Cardiovascular Research 2007 74(2):181-183; doi:10.1016/j.cardiores.2007.03.011
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Copyright © 2007, European Society of Cardiology

The TGFβ superfamily in cardiovascular biology

Jawahar L. Mehtaa,* and Håvard Attramadalb

aDepartment of Internal Medicine and Physiology and Biophysics, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA
bInstitute for Surgical Research, Rikshospitalet University Hospital, Oslo, Norway

* Corresponding author. Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, 4301 West Markham St., Slot 532, Little Rock, 72205-7199 AR, USA. Tel.: +1 501 296 1401; fax: +1 501 686 8319. Email address: MehtaJL{at}uams.edu

Received 9 March 2007; accepted 12 March 2007


   1. The biology of the TGFβ superfamily
Top
 1. The biology of...
2. TGFβ and atherosclerosis
 3. Myocardial ischemia and...
 References
 
This issue of Cardiovascular Research is focused on the TGFβ superfamily and cardiovascular disease. It is timely to comment on some of the unique aspects of this potent cytokine family in relation to cardiovascular disease. There are three structurally similar isoforms of TGFβ, encoded by three distinct genes, in mammalian species; of these, TGFβ1 is the most prevalent. The TGFβ superfamily also includes several other related growth factors, including activin, GDF-15, several bone morphogenetic protein (BMP) isoforms, and nodal. Apparently, all TGFβ superfamily members bind to heterodimeric receptor isomers that belong to the same family, i.e. dimeric complexes of various type I receptor serine/threonine kinases (ALK 1-7) and type II receptor proteins (5 isoforms). These receptors subsequently activate different intracellular Smad proteins to elicit various biological responses [1]. Besides activation of Smads, TGFβ mediates its effects via activation of a number of signals including p38 MAPK, Erk, JNK, and TAK1. This pathway has been reviewed elegantly by Bujak and Frangogiannis in this issue of the Journal [2]. Except for TGFβ itself, the biological functions of the other TGFβ superfamily ligands are poorly understood or have only been partly elucidated.

TGFβs are among the most multifunctional cytokines known; they affect a variety of cell types and modulate multiple biological processes. TGFβ1 knockout mice have a defect in embryonic Development and immune regulation [3]. With regard to the cardiovascular system, low concentrations of TGFβ are growth promoting, and high concentrations are growth inhibitory via modulation of PDGF-A and PDGF-B receptors in smooth muscle cells (reviewed by Ruiz-Ortega et al. in this issue, see Ref. [4] and references therein). Very low concentrations of TGFβ1 induce chemotaxis of neutrophils [5] and monocytes [6], but result in diminished leukocyte adhesion and migration [7,8]. The overall effect of TGFβ depends on the cytokine milieu and the state of cell differentiation. Further, TGFβ can be both pro-angiogenic and angiostatic, depending on the source of endothelial cells and concentration [2].

There is potent interaction between TGFβ and the renin–angiotensin system. The effector hormone of the renin–angiotensin system angiotensin II (Ang II) enhances, via MAPK activation, endoglin, a component of TGFβ1 type 3 receptor, as well as type 1 and 2 receptors. Renin–angiotensin system activation is involved in atherogenesis as well as myocardial ischemia injury. Like TGFβ1, Ang II is a pro-fibrotic stimulus, and it is possible that Smads are activated in response to Ang II [4]. It is of note that many of the signaling pathways in Ang II effects are mediated by TGFβ. Further, as discussed here in a review by Leask [9], TGFβ may interact with other cytokines such as connective tissue growth factor and endothelins, leading to fibrosis.


   2. TGFβ and atherosclerosis
Top
 1. The biology of...
 2. TGFβ and atherosclerosis
3. Myocardial ischemia and...
 References
 
There is a renewed interest in the potential of growth factors to limit atherosclerosis and its major manifestation, myocardial ischemia. Grainger et al. [10] showed that levels of transforming growth factor β1 (TGFβ1) are reduced in patients with atherosclerosis. Recombinant TGFβ1 has been shown to reduce cardiac injury following ischemia-reperfusion and to alter the signals of tissue remodeling [11]. How growth factors modulate atherogenesis and molecular signals in the ischemic heart is a subject of intense investigation. Naturally, any advance in this field will have major therapeutic implications.

Atherosclerosis is a biological process accompanied by an extensive inflammatory response and oxidative stress. The inflammatory response is characterized by monocyte/macrophage adhesion to activated endothelial cells, rolling along the activated endothelial cells, and transmigration to sub-endothelial space, where they phagocytose oxidized lipids via scavenger receptors and become foam cells. A state of enhanced oxidative stress beyond the capacity of endogenenous antioxidants to scavenge free radicals is also a prominent feature of atherosclerosis from its beginning to the culmination in an acute event, such as acute myocardial infarction. In addition, there is activation of smooth muscle cells, which develop leukocyte adhesion molecules and proliferate. There is also formation of extracellular matrix (ECM), which influences the architecture of the vessel wall. TGFβ1 stimulates ECM production by smooth muscle cells in culture [12]. It also reduces expression of adhesion molecules on endothelial cells in culture [13], which has an indirect suppressive effect on the inflammatory reaction in the vessel wall. TGFβ1 has a range of effects on immune cells, including inhibition of foam cell formation in cultured macrophages [14]. Indeed, TGFβ over-expression has been shown to reduce atherogenesis in experimental animals [15,16]?, and reduced availability of TGFβ1 ligands leads to pro-atherogenic changes [17]. Similarly, use of anti-TGFβ1 antibodies leads to increased inflammation, lipid deposition, and a shift towards an unstable plaque phenotype [18]. The relationship of TGFβ with atherosclerosis in animal models and humans has been discussed in detail by Grainger in this issue of the Journal [19].

On the other hand, there is recent evidence suggesting that antagonizing TGFβ1 activity with direct or indirect inhibitors may attenuate or prevent intimal thickening. This has been addressed by Khan et al. in this issue [20]. These observations are in contrast to the studies discussed by Grainger [19], suggesting modulation of atherosclerosis by TGFβ1. Again, studies are urgently needed to discern the effects of this cytokine in modulation of the arterial response following injury.


   3. Myocardial ischemia and cardiac remodeling
Top
 1. The biology of...
 2. TGFβ and atherosclerosis
 3. Myocardial ischemia and...
References
 
Many of the processes involved in determination of myocardial ischemic injury are the same as in atherosclerosis. Reperfusion following a brief period of ischemia triggers a cascade of events leading to oxidative stress and an inflammatory reaction. Both oxidative stress and the inflammatory response are potent signals for cardiac remodeling characterized by formation of collagens and collagen-degrading enzymes, also known as matrix metalloproteinases (MMPs).

In vitro experimental work has shown potent anti-oxidant and anti-inflammatory effects of TGFβ1 in endothelial cells and cardiomyocytes. In vivo studies have shown that TGFβ1 up-regulation reduces ultimate myocardial infarct size (see review by Hermonat et al. [21]).

It is of note that TGFβ1 is over-expressed following acute ischemia, which is probably a tissue-protective response to ischemia. Notably, TGFβ1 expression is attenuated by angiotensin converting enzyme inhibitors and Ang II receptor blockers [22,23], suggesting a link between renin–angiotensin system activation and TGFβ1 expression. TGFβ is localized in the peri-infarct zone [24]. There is also increased expression of Smads in the healing infarct. TGFβ1 (and BMP-2) expression may direct embryonic stem cells towards differentiated cardiac myocytes. This has been addressed in detail by van Wijk et al. [25] and Puceat [26] in this issue of the Journal.

TGFβ1 over-expression reduces signals for collagens and MMPs, which may influence the cardiac remodeling process during chronic ischemia [21]. However, the specific role of TGFβ1 in altering the cardiac remodeling process is not known. Studies using long-term over-expression of TGFβ as outlined by Hermonat [21] will shed light in this arena. Certainly, data from TGFβ inhibition strategies suggest that treated animals have enhanced neutrophil infiltration and increased mortality.

There has been concern about the profibrotic effects of TGFβ1. However, it may be speculated that reduction in acute ischemic insult may remove the trigger for collagen formation. Some of the issues related to cardiac remodeling are discussed in this issue of the Journal [2]. Nonetheless, the primary effect of TGFβ as a profibrotic cytokine may have a bearing on overall cardiac remodeling after tissue ischemia [9] and needs to be evaluated in animal models.


   References
Top
 1. The biology of...
 2. TGFβ and atherosclerosis
 3. Myocardial ischemia and...
 References
 

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