THIAZOLIDINEDIONES AND VASCULAR MYOCYTE METABOLISM

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Atherosclerotic ischemic heart disease is the major cause of death in western industrialized countries. Despite a failure rate of 30-50% due to restenosis, coronary angioplasty is emerging as the treatment of choice. The pathology underlying atherosclerosis and restenosis is an inflammatory-fibroproliferative remodeling process in which vascular smooth muscle (VSMC) cells inappropriately de-differentiate, migrate, proliferate and synthesize extracellular matrix (ECM) proteins in response to multiple growth regulatory factors released locally. The result is formation of obstructive neointimal lesions in the coronary vessels. Our long term goal is to study the functional modulation of human VSMC by PDGF and TGF-beta1 under basal and "synthetic" conditions. In the synthetic phenotype, VSMC exhibit hyper-proliferative, chemotactic and protein synthetic properties similar to those seen in atherosclerotic and restenotic lesions. The effects of these growth factors on indices of proliferation (3H-thymidine incorporation, c-myc and c-myb expression), cell migration and quantitative and qualitative aspects of protein synthesis in synthetic human VSMC will be used as a quantitative estimate of the processes underlying the pathological lesion in vivo. There is no efficacious drug presently available to treat or prevent atherosclerosis or restenosis. The thiazolidinediones are a class on insulin-sensitizing, anti-dyslipidemic, antihypertensive drugs presently in human trials for these indications. These molecules inhibit proliferation of rodent VSMC in vitro. We propose to extend these studies to cultured human aortic VSMC (HAVSMC) measuring the parameters described above.