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Background-The proliferation of vascular smooth muscle cells (VSMCs) is a known response to arterial injury that is an important part of the process of restenosis and atherosclerosis. People with diabetes have an increased risk of cardiovascular disease resulting from accelerated coronary atherosclerosis. The newest drugs for Type 2 diabetes are thiazolidinediones, which are insulin-sensitizing peroxisome proliferator activating receptor-␥ (PPAR␥) ligands. We investigated the antiproliferative effects of troglitazone, rosiglitazone, and pioglitazone on VSMCs derived from the three vascular beds used for coronary artery by-pass grafting: the internal mammary and radial artery and saphenous veins. Methods and Results-The three vessels yielded proliferating cells of slightly differing morphology. Inhibition of cell proliferation was assessed by cell counting and cell cycle studies by Western blotting for phosphorylated retinoblastoma protein.All three thiazolidinediones showed inhibitory potency toward cell proliferation with a potency troglitazoneϾrosiglitazoneϷpioglitazone, and this potency profile was maintained toward the growth factor and insulin-stimulated phosphorylation of the retinoblastoma protein, which controls cell cycle progression. Key Words: muscle, smooth Ⅲ diabetes mellitus Ⅲ restenosis Ⅲ grafting P roliferation of vascular smooth muscle cells (VSMCs) is an important response to arterial injury and contributes to the formation of atherosclerotic lesions and coronary heart disease (CHD), 1 and the process is markedly accelerated in the setting of diabetes. 2 The main methods of treatment for CHD are angioplasty and coronary artery bypass grafting (CABG). The three most common vessels used in CABG are internal mammary artery (IMA), radial artery (RA), and saphenous veins (SV). [3][4][5] Individuals with diabetes experience hyperproliferation of VSMCs limiting angioplasty, 6 and some consider that the preferred line of intervention in this group is CABG. Thiazolidinediones (TZDs), ligands for peroxisome proliferatoractivated receptor-␥ (PPAR␥), 7,8 are the latest group of therapeutic agents for the treatment of Type 2 diabetes. TZDs inhibit the proliferation of VSMCs 8,9 but whether the inhibitory activity is dependent on the particular PPAR␥ agent or the vascular bed from which the cells are derived is unknown. Conclusion-TheWe investigated the effects of troglitazone (TRO), rosiglitazone (ROSI), and pioglitazone (PIO) on the proliferation of VSMCs derived from IMA, RA, and SV. The order of potency was TROϾROSIϷPIO, which was the same in each vascular smooth muscle cell preparation, and thus it is the particular TZD, not the vascular bed, that determines the inhibitory response. Methods MaterialsTroglitazone was obtained as a gift from Parke Davis Pharmaceutical Research, Ann Arbor, Mich, rosiglitazone from SmithKline Beecham International, Australia, and pioglitazone was donated by Eli Lilly Pharmaceuticals. VSMC PreparationsPrimary human VSMCs were isolated by the explant technique from IMA, RA, a...

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The formation and progression of atherosclerotic plaques followed by rupture, thrombus formation and vessel blockage leads to ischemic tissue damage and the clinical condition underlying most cardiovascular disease. Therapeutic agents for the prevention of atherosclerosis have all targeted epidemiologically-identified and relatively easily measured risk factors (e.g. lipids and blood pressure). This strategy has proven somewhat effective but is of less than optimal efficacy as rates of cardiovascular disease remain high. Treatment targeting the mechanisms of atherosclerosis in the vessel wall is a conceptually attractive proposition to complement the risk factor directed strategy. Vascular smooth muscle cells (VSMC) are the major cellular component of the vascular media and migration and proliferation leads to the formation of the neointima the development of which renders the vessels particularly sensitive to atherosclerosis. Numerous hormones and growth factors act on VSMC to cause migration, proliferation and the secretion of extracellular matrix and modulation or dysfunction of these processes is the most likely cause of atherosclerosis. Endothelin-1 (ET-1) is a 21 amino acid peptide that acts on 7 transmembrane G protein coupled receptors to elicit a plethora of responses that can modulate the behaviour of VSMCs and thus impact on the development of atherosclerosis. ET-1 is elevated in atherosclerotic plaques. People with diabetes have accelerated atherosclerosis and also show elevated plasma levels of ET-1. This review addresses the actions of ET-1 on VSMC and the signalling pathways through which it mediates its effects as the latter represent potential therapeutic targets for the prevention of atherosclerosis.