The Role of TGF- and TGF- Receptors in Atherosclerosis

Researchers discovered a new cytokine with the capability to transform fibroblasts in 1983 while studying epidermal and platelet derived growth factors in rat fibroblasts. Originally called sarcoma growth factor, TGF┚ was first isolated from neoplastic mouse tissue by Moloney sarcoma virus (Assoian et al., 1983). After more than three decades TGF-┚ family comprise several members including – nodals, activins, bone morphogenic proteins (BMPs), myostatin, anti-Muellerian hormone (AMH) and others – control cell division, differentiation, migration, adhesion, organization and programmed cell death (Massague, 1998). There are three TGF-┚ isoforms currently described in humans, including TGF-┚1, TGF-┚2, and TGF-┚3. Alignment of the amino acid sequences of the three mammalian TGF-┚ isoforms reveals that the different isoforms share a high level of similarity between the active domains; TGF┚3 is 86% similar to that of TGF┚1 while it shares 91% similarity with that of TGF-┚2. However, despite TGF┚2 and ┚3 sharing the highest level of sequence similarity of the three isoforms, TGF┚2 binds to the TGF-┚ receptor II (T┚RII) in a different way from TGF ┚1 and ┚3. Furthermore, while TGF-┚1 and -┚3 are both capable of binding directly to the type II receptor, presentation of TGF-┚2 to the receptor requires the presence of a co-receptor (beta glycan or endoglin), which may explain the differences in activities of TGF-┚2 and -┚1 (Laverty et al., 2009). The importance of TGF-┚ isoforms in mammalian biology is highlighted by the lack of viability in TGF-┚−/− mice. Targeted disruption of the TGF-┚1 genes leads to hematopoietic and vasculogenic defects that result in death of about half of null embryos by 10 days gestation. Moreover, embryos that survive die within 3 weeks due to widespread inflammatory disease (Shull et al., 1992). TGF-┚2 null mice die in the perinatal period due to cyanotic heart disease, pulmonary insufficiency, and another abnormalities in urogenital, visual, auditory, neural and skeletal systems (Sanford et al., 1997). Additionally, mice lacking TGF-┚3 exhibit cleft palate with 100% penetration and die immediately after birth due to an inability to suckle effectively (Proetzel et al., 1995). In addition, other organs are not affected when compared with mice lacking TGF-┚1 and TGF-┚2. Several other papers showed differences in postnatal effects of different TGF-┚ isoforms, including different role in neovascularization (Wu et al., 1997), collagen production and bone production (ten Dijke et al., 1990). Moreover, TGF-betas are released by immune cells