Retinoids: new insight into smooth muscle cell growth inhibition.

Abstract

The successful management of vascular occlusive diseases, particularly those due to procedural interventions for preexisting atherosclerosis, will likely require the targeting of numerous cellular processes rather than any 1 gene, protein, or signaling pathway. This fact is underscored by the failure of virtually all clinical trials employing pathway- or factor-specific therapeutics to limit restenosis after percutaneous vascular interventions. Retinoids are natural and synthetic derivatives of vitamin A that exert myriad effects on such cellular processes as growth, apoptosis, differentiation, and migration. As such, retinoids could be potential therapeutics to test in the context of vascular occlusive disease.1 2 3 4 Clinically, the prototypic natural retinoid, all- trans retinoic acid (atRA), effects a nearly 100% rate of remission in patients with acute promyelocytic leukemia.5 Given the similarities in the pathogenesis of neoplasia and vascular occlusive lesions (ie, increased cell growth and loss of cellular differentiated properties), it is surprising that retinoids have only recently been examined with respect to cells of the vascular wall. Many retinoids exert their pleiotropic effects through the binding and activation of nuclear retinoid receptors. There are 2 families of retinoid receptors, each of which comprises 3 distinct genes. The retinoic acid receptors (RAR α, β, and γ) bind atRA and its 9- cis stereoisomer (9cRA), whereas the more weakly expressed retinoid X receptors (RXR α, β, and γ) bind 9cRA.6 Numerous retinoids have been synthesized and tested for receptor selectivity as a means of reducing the side effects associated with natural retinoid therapy. Many of these synthetic retinoids have recently found clinical utility for a number of diseases.4 Ligand-activated retinoid receptors dimerize (preferentially as an RAR-RXR heterodimer), recognize, and bind cis elements (called retinoic acid–response elements, or RAREs) in the genome to activate gene transcription. Identifying retinoid-responsive target genes is critical in …