Transforming growth factor-β and atherosclerosis: interwoven atherogenic and atheroprotective aspects

Abstract

Age-related progression of cardiovascular disease is by far the largest health problem in the US and involves vascular damage, progressive vascular fibrosis and the accumulation of lipid-rich atherosclerotic lesions. Advanced lesions can restrict flow to key organs and can trigger occlusive thrombosis resulting in a stroke or myocardial infarction. Transforming growth factor-beta (TGF-β) is a major orchestrator of the fibroproliferative response to tissue damage. In the early stages of repair, TGF-β is released from platelets and activated from matrix reservoirs; it then stimulates the chemotaxis of repair cells, modulates immunity and inflammation and induces matrix production. At later stages, it negatively regulates fibrosis through its strong antiproliferative and apoptotic effects on fibrotic cells. In advanced lesions, TGF-β might be important in arterial calcification, commonly referred to as “hardening of the arteries”. Because TGF-β can signal through multiple pathways, namely the SMADs, a MAPK pathway and the Rho/ROCK pathways, selective defects in TGF-β signaling can disrupt otherwise coordinated pathways of tissue regeneration. TGF-β is known to control cell proliferation, cell migration, matrix synthesis, wound contraction, calcification and the immune response, all being major components of the atherosclerotic process. However, many of the effects of TGF-β are essential to normal tissue repair and thus, TGF-β is often thought to be “atheroprotective”. The present review attempts to parse systematically the known effects of TGF-β on both the major risk factors for atherosclerosis and to isolate the role of TGF-β in the many component pathways involved in atherogenesis.

Endothelial-to-mesenchymal transition drives atherosclerosis progression

“…In contrast, restoration of effective endothelial FGF signaling and/or suppression of endothelial TGF-β signaling may effectively halt the disease progression. The latter points to the complexity of endothelial biology, as smooth muscle TGF-β signaling has been linked to reduction in atherogenesis (32,33) and may explain the ambiguous nature of TGF-β effects in atherosclerosis (34). turbed shear stress, decrease endothelial FGFR1 expression, leading to activation of TGF-β signaling, thereby inducing EndMT.…”

TGF-β in aging and disease

“…In their review, Toma and McCaffrey (2011) discuss the role of TGF-β as a major orchestrator of the vascular fibroproliferative response. In the early stages of repair, TGF-β is released from platelets and activated from matrix reservoirs.…”

Identification of candidate genes encoding an LDL-C QTL in baboons

“…Evidence indicates that dietary cholesterol induces hepatic infl ammation ( 44 ), and our study suggests that the ACVR / SMAD pathway could be involved and modulated by ACVR1B to trigger an anti-infl ammatory response. ACVR1B lacks an active tyrosine kinase domain; thus, when bound by activin, the receptor recruits type II activin receptor to activate SMAD 2/3 complex, which interacts with SMAD4 to regulate transcription activity of CTNNB1 ( ␤ -catennin), a coactivator for TCF/ LEP transcription factors that control expression of interleukin cytokines and cell-cycle control genes, such as CDK activators and inhibitors ( 45 ). Thus, the ACVR / SMAD pathway may infl uence a plethora of biological processes depending on cell type and context.…”

“…ACVR1B is a member of the transforming growth factor-␤ receptor ( TGFR ) family of receptors that are master regulators of infl ammation, cell proliferation, and differentiation ( 46 ). Moreover, both ACVR1B and TGFR are transducers of ACVR / SMAD pathway and are anti-inflammatory, which explains the alleviation of TGFR in atherosclerosis patients ( 45,47 ). Supplemental Material can be found at:…”