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STATE-OF-THE-ART PAPER

New aspects in the pathogenesis of diabetic atherothrombosis

Pedro R. Moreno, MD^*,,* and Valentin Fuster, MD, PhD^*

^* Zena and Michael Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York
Gill Heart Institute, University of Kentucky, Lexington, Kentucky

Manuscript received April 2, 2004; revised manuscript received May 20, 2004, accepted July 5, 2004.

^* Reprint requests and correspondence: Dr. Pedro R. Moreno, Cardiovascular Institute, Mount Sinai School of Medicine, P.O. Box 1030, One Gustave L. Levy Place, New York, New York 10029 (Email: Pedro.Moreno{at}msnyuhealth.org).

Diabetes mellitus is increasing worldwide, resulting from the interaction of obesity, inflammation, and hyperglycemia. Activated immunity and cytokine production lead to insulin resistance and other components of the metabolic syndrome, establishing the link between diabetes and atherosclerosis. Hyperglycemia-induced endothelial dysfunction is mediated by increased oxidative stress, a promoter of adventitial inflammation and vasa vasorum neovascularization in experimental models of diabetic atherosclerosis. Recent studies have documented increased inflammation, neovascularization, and intraplaque hemorrhage in human diabetic atherosclerosis. This inflammatory microangiopathic process is independently associated with plaque rupture, leading to coronary thrombosis. Tissue factor, the most potent trigger of the coagulation cascade, is increased in diabetic patients with poor glycemic control. Circulating tissue factor microparticles are also associated with apoptosis of plaque macrophages, closing the link among inflammation, plaque rupture, and blood thrombogenicity. High-density lipoproteins, responsible for free cholesterol removal, are reduced in patients with insulin resistance and diabetes. High-density lipoprotein therapy leads to a significant decrease in plaque macrophages and increase in smooth-muscle cells. These beneficial effects may be responsible for coronary plaque stabilization in patients treated with recombinant Apolipoprotein A-I Milano/phospholipid complex. Finally, peroxisomal proliferator-activated receptors (PPARs) are now considered the nuclear transcriptional regulators of atherosclerosis. Three subfamilies, including PPAR-alpha, -delta, and -gamma, have been identified with crucial roles in lipid metabolism, plaque inflammation, expression of adhesion molecules and cytokines, and regulation of matrix metalloproteinases. Multiple experimental studies have documented plaque stabilization with PPAR-gamma agonists, a group of medications holding great promise in the treatment of diabetes atherosclerosis.

Abbreviations and Acronyms   AGE = advanced glycation end product   HDL = high-density lipoprotein   MMP = matrix metalloproteinase   PPAR = peroxisomal proliferator-activated receptor   ROS = reactive oxygen species   TF = tissue factor

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