The complex regulation of TGF-β in cardiovascular disease

Abstract

Transforming growth factor β (TGF-β1) is a pleiotropic cytokine with many and complex effects in cell and tissue physiology. This is made possible by a very complex and interwoven signaling system, whose regulation continues to be the focus of a growing line of research. This complex regulation translates to a key role in cardiovascular physiology, hemostasis, and the blood-vessel interface. In accordance with this, the TGF-β1 pathway appears to be deregulated in related disorders, such as atherosclerotic vascular disease and myeloproliferative syndromes. It is expected that the growing amount of experimental and clinical research will yield medical advances in the applications of knowledge of the TGF-β1 pathway to diagnosis and therapeutics.

Keywords: Smads; atherosclerosis; myeloproliferative syndromes; non-Smads; pathway; transforming growth factor beta.

Figure 1

Summary of the main regulators of the TGF-β pathway. Notes: Briefly, TGF-β binds to receptor type 2 and phosphorylates the type 1 receptor, whose main isoform is termed ALK-4 (activin-like kinase). This kinase phosphorylates and activates Smad2 or Smad3, which forms a heterodimer with Smad4, and internalizes into the nucleus to regulate gene expression. TGF-β can also act by means of non-Smad mediators, such as p38 MAP kinase and Small GTPases, like RhoA. Cytoskeleton and receptor endocytosis are additional mechanisms to regulate the TGF-β signaling. Gene expression can also be eventually modified by micro-RNAs. Abbreviatons: TGF-β, transforming growth factor beta; Smad, second messenger protein; ALKs, activin-like kinases.