Pathophysiology of Diabetic Retinopathy and Alpha-V-Beta3 Integrin Receptor Antagonist [Tetra-Iodothyroacetic Acid (Tetrac)] Roles as Antiangiogenic and Anti-Inflammatory

Abstract

Integrins are large, transmembrane glycoproteins, well-known as cell surface receptors that are essential in cell-to-cell interactions and thus to tissue structure. Integrins provide mechanical attachments between cells and the extracellular matrix (ECM) and other cells, and generate bidirectionally (inside-out and outside-in) cellular signals. so integrins have been proved to regulate cellular growth, proliferation, migration, signaling, and apoptosis, tissue repair, as well as in all processes critical to inflammation, infection, and angiogenesis. ,5,3′,5′ tetraiodothyroacetic acid (tetrac, TA4) is a naturally occurring, analogue of thyroid hormone (L-thyroxine, T4) that accounts for less than 1% of circulating thyroid hormones. For 30 or more years, tetrac has been known to be taken up by pituitary cells that secrete thyrotropin (TSH) and to inhibit endogenous human TSH release by the pituitary gland. This action has been considered potentially useful in the clinic in the setting of TSH-dependent thyroid cancer. As tetrac may undergo nuclear uptake and, in the nuclear compartment, tetrac has low-grade thyromimetic activity, a nano-formulation of tetrac called nanotetrac or nano-diamino-tetrac (NDAT) is formed by covalently bonding tetrac to a 150–200 nm poly lactic-co-glycolic acid (PLGA) nanoparticle. Tetrac has been described as an anti-angiogenic agent as it blocks the proangiogenic action of thyroid hormones on integrin αvβ3. But even in the absence of T4 and T3, tetrac and its nano-formulation also block the pro-angiogenic effect of different growth factors-mediated angiogenesis as vascular endothelial growth factor (VEGF), basic fibroblast growth factor-2 (bFGF-2) and platelet-derived growth factor via integrin αVβ3 antagonism. Tetrac has shown to have antioxidants effect. Tetrac reveals high free radical scavenging capacities greater than those of T3 and protects LDL from peroxidation. Tetrac has shown to have anti-inflammatory effects through regulation of the expression of some inflammation-related genes.