Meta-iodobenzylguanidine, investigations into a mechanism of action and application to restenosis
Failure of revascularization procedures for the treatment of coronary artery disease, such as balloon angioplasty, typically occurs as a result of restenosis, a renarrowing of the lumen at the site of intervention. Restenosis is characterized by the formation of a neointimal lesion, a process that involves migration of smooth muscle cells from the medial to intimal region of a blood vessel followed by cell proliferation and extracellular matrix deposition. No intervention to date has proven to be clinically significant with regards to efficacy. As a result, a unique compound, MIBG, that inhibits post-translational modification of proteins associated with signal transduction pathways that modulate cell migration, proliferation and differentiation was investigated. H4IIE hepatoma cells were used to establish that MIBG inhibited cell growth and proliferation. MIBG was also shown to prevent differentiation of L6 skeletal myoblasts into myotubes, an effect that was reversible on removal of the compound. The effect of MIBG on differentiation was found to be a consequence of its action on the expression of key elements in the myogenic program. Smooth muscle cells are the primary cell type involved in the events leading to restenotic lesion formation, and studies with MIBG demonstrated that this compound is capable of inhibiting both smooth muscle cell migration and proliferation in response to growth factors and other stimulating agents. Furthermore, there was an indication that the compound may affect several signaling pathways in smooth muscle cells, as demonstrated by MIBG-dependent inhibition of PGE 2-mediated c-'fos' gene expression. An organ culture model of balloon angioplasty was used to show that MIBG is capable of inhibiting restenosis under controlled experimental conditions. Finally, femoral angioplasty ' in vivo' was sed to confirm the data generated with the organ culture model in a physiologically relevant system. MIBG significantly reduced neointimal formation in the injured regions of a porcine femoral artery when compared to arteries without MIBG treatment. These studies indicate that the inhibition of cell migration, proliferation and differentiation by MIBG may be beneficial in the treatment of restenosis post-angioplasty and therefore applicable to therapeutic intervention in a clinical setting.