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Background
The prevalence of diabetes among adults worldwide was estimated in 2010 to 6.4%, thus affecting 285 million adults. This figure is predicted to rise to 7.7%, in numbers 439 million, by 2030. In patients with diabetes, the major cause of death is macrovascular disease, and in individuals with type 2 diabetes, the main etiology for up to 75% of the mortality is atherosclerotic cardiovascular disease. In contrast to microangiopathies (e.g. nephropathy and retinopathy), where the causal relation to hyperglycemia is well supported, the link between hyperglycemia and macroangiopathy is uncertain, at least in terms of the possibility of reducing macrovascular morbidity solely by reducing hyperglycemia. Most patients with diabetes are consequently being treated with one or more antidiabetic drugs, a lipid-lowering statin and an ACE inhibitor or angiotensin receptor antagonist for hypertension and/or albuminuria.
The endothelium is composed of a monolayer of cells that line the lumen of blood vessels and form a physical barrier between circulating blood and the vascular smooth muscle cells. The endothelium plays a very important role in maintenance of vascular integrity by protecting the vessels from activation of clotting and proinflammatory factors. It also participates in the regulation of blood flow and blood pressure. Loss of physiological features of the endothelium, such as its preference to support vasodilatation, fibrinolysis and antiaggregation, is referred to as endothelial dysfunction, which has been observed in diabetes (type 1 and type 2), in obesity and in patients with insulin resistance. In fact, the extent of endothelium-dependent vasodilatation correlates in obese and insulin resistant subjects with their individual insulin sensitivity. Endothelial dysfunction has thus emerged as an important early target for preventing atherosclerosis and cardiovascular disease.
Hyperglycemia and hyperlipidemia are important factors in the development of endothelial dysfunction. Free fatty acids (FFAs), formed during lipolysis from triglycerides, and hyperglycemia are known to impair the endothelial-dependent vasodilatation. Increased plasma levels of FFAs and glucose are characteristic features in patients with type-2 diabetes. Both factors are known induce apoptosis of endothelial cells and endothelial cell death is believed to be involved in, and contribute to, endothelial dysfunction and atherosclerosis.
Current anti-diabetes drugs are mainly aimed to correct hyperglycemia by promoting pancreatic β-cell insulin secretion, increasing insulin sensitivity, or reducing intestinal glucose uptake and hepatic gluconeogenesis. Apart from insulin, glimepiride, a third generation sulfonylurea, pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, and a member of the thiazolidinedione family (TZD), and metformin, a biguanide, are used for treatment of type 2 diabetes. Candesartan, an angiotensin II receptor antagonist, and rosuvastatin, a competitive inhibitor of the enzyme HMG-CoA reductase, are used for management of hypertension and hyperlipidemia, respectively. In addition, we have also studied BLX-1002, a novel thiazolidinedione with no structural resemblance to other TZDs, which does not appear to affect PPARs. There is evidence that BLX-1002 can improve hyperglycemia in diabetic animal models without the body weight gain typically associated with PPARγ-mediated adipocyte differentiation. Not much is known about BLX-1002, but it has been shown to potentiate insulin secretion from islets in a phosphatidylinositol 3-kinase (PI3K)-dependent manner. BLX-1002 also activates AMP-activated protein kinase (AMPK) perhaps through its ability to inhibit the mitochondrial complex 1.
Compared to studies on the actions of the above drugs on glycemia, little has been done regarding their direct actions on proliferation and apoptosis of human coronary artery endothelial cells (HCAECs). Understanding the effects of these agents is important as endothelial growth and apoptosis are involved in endothelial repair and function. Disruption of the intimal layer subjects the arterial wall to greater risk for macrovascular disease, the most common etiology for morbidity and mortality in diabetic patients. Therefore, the aim of our study was to investigate the effects of drugs used in treatment of diabetic patients on proliferation and lipotoxicity-induced apoptosis in HCAECs.
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