Prevention Conference VI: Diabetes and Cardiovascular Disease: Writing Group II: pathogenesis of atherosclerosis in diabetes.

Abstract

Diabetes is associated with increased atherosclerosis and other causes of myocardial dysfunction. The pathogenesis of cardiovascular disease (CVD) in diabetes is multifactorial and can be affected by metabolic and other factors. Under physiological conditions, the endothelial cell (EC) layer acts as a barrier to separate circulating factors and cells from the arterial intima and media. It also serves as an anticoagulant and fibrinolytic surface producing tissue plasminogen activator, which counters the effects of procoagulant factors such as fibrinogen and plasminogen activator inhibitor-1 (PAI-1). Endothelial cells produce nitric oxide (NO), which is a vasodilator and restrains smooth muscle cell (SMC) migration and proliferation. Circulating factors (hyperglycemia, increased free fatty acids, altered lipoproteins, and derivatives of glycation and oxidation) and hypertension, all of which are common in diabetes, can damage ECs, leading to their dysfunction. Plasma proteins, among them lipoproteins, cross the endothelial barrier, where they can be retained by subendothelial matrix molecules such as collagen and proteoglycans.1 These and other matrix molecules are produced by ECs and SMCs. Blood components can be modified, eg, by oxidation and glycation.2 Modified proteins and lipids can alter EC and SMC gene expression, leading to increased production of procoagulants, adhesion molecules, chemotactic factors, and cytokines. The net effect is the adhesion and penetration of circulating monocytes into the arterial intima, where they undergo differentiation and activation to macrophages. Lipids can accumulate intracellularly after uptake of modified lipoproteins (glycation, oxidation, and glycoxidation) by different scavenger receptors on macrophages and SMCs, as well as extracellularly by attaching to matrix molecules.3 The resulting lesion is termed the fatty streak. Both ECs and macrophages produce cytokines and growth factors that permit SMCs to migrate from the media to the intima. In the intima, SMCs proliferate in response to several growth factors. These SMCs and the matrix …