Basic Science Review: Statin Therapy-Part I: The Pleiotropic Effects of Statins in Cardiovascular Disease

3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA-reductase) inhibitors, otherwise known as statins, are currently the medical treatment of choice for hypercholesterolemia. Hypercholesterolemia is a known risk factor for cardiovascular disease, and statin therapy has led to a significant reduction in morbidity and mortality from adverse cardiac events, stroke, and peripheral arterial disease. In addition to achieving a therapeutic decrease in serum cholesterol levels, statin therapy appears to promote other effects that are independent of changes in serum cholesterol. These ‘‘pleiotropic’’ effects include attenuation of vascular inflammation, improved endothelial cell function, stabilization of atherosclerotic plaque, decreased vascular smooth muscle cell migration and proliferation, and inhibition of platelet aggregation. This article is part I of a 2-part review, and it focuses on the pleiotropic effects of statins at the cellular level. </jats:p

Thrombospondin-1: A proatherosclerotic protein augmented by hyperglycemia

ObjectiveDiabetes is associated with a more aggressive form of atherosclerosis. Thrombospondin-1 (TSP-1), an extracellular matrix protein, is an acute-phase reactant that induces vascular smooth muscle (VSMC) migration and proliferation in areas of vascular injury and is also up-regulated in VSMCs exposed to hyperglycemia. This study tested the hypothesis that hyperglycemia amplifies the expression of genes induced by TSP-1 in VSMCs.MethodsHuman aortic VSMCs were cultured in Dulbecco Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% antibiotics. Cells were used between passages three and five. VSMCs were preincubated in DMEM containing 0.2% FBS with 5 mM glucose (normoglycemia), 25 mM glucose (hyperglycemia), 25 mM mannose (osmotic control), TSP-1 (20 μg/mL), 25 mM glucose + TSP-1 (20 μg/mL), or 25 mM mannose + TSP-1 (20 μg/mL). Total RNA was extracted. Microarray analysis was performed and analyzed by analysis of variance. P < .05 was considered significant. Quantitative real-time polymerase chain reaction (rtPCR) was used to confirm selected up-regulated genes.ResultsMicroarray analysis revealed: (1) hyperglycemia altered 30 genes; (2) TSP-1 altered 212 genes, of which 8 were altered similarly to VSMCs exposed to 25 mM glucose; (3) TSP-1 up-regulated 10 genes associated with atherosclerosis and 4 others with diabetic vascular disease; (4) hyperglycemia combined with TSP-1 altered expression of 2822 genes. The three genes most up-regulated by TSP-1 in a normoglycemic environment were uridine 5′-diphosphoglucose (UDP-glucose) dehydrogenase (UGDH, 127%), transforming growth factor β-2 (TGFβ2, 116%), and hyaluronan synthase 2 (HAS2, 113%). Further, TSP-1 altered the expression of genes in 13 canonical pathways; however, when combined with hyperglycemia, 53 canonical pathways were affected.ConclusionQuantitative rtPCR confirmed that genes in several of these pathways for TSP-1 and hyperglycemia combined with TSP-1 were up-regulated. These findings suggest that TSP-1 may be germane to the progression of atherosclerosis and may have a large effect with concurrent hyperglycemia.Clinical RelevanceDiabetes is increasing rapidly in the United States. One of the characteristics of this disease is accelerated atherosclerosis. Thrombospondin-1 (TSP-1) has been shown to be involved in atherosclerosis and up-regulated in the tissues of diabetic patients and in animal models of diabetes. Among other actions, TSP-1 has been shown to increase DNA synthesis in vascular smooth muscle cells; however, the specific genes increased have not been completely identified. Further, the influence of hyperglycemia on TSP-1–induced gene expression has not been fully determined. The present study demonstrates that TSP-1 causes the up-regulation of several genes involved in atherosclerosis and diabetes and that hyperglycemia has a substantial effect on this process. Understanding the apparent complex interaction between hyperglycemia and TSP-1 will help identify therapeutic targets and aid in the development of anti-TSP-1 strategies to reduce vascular disease in diabetes