Laboratory Overview

  Complications of atherosclerotic vascular disease are the leading cause of death in industrialized countries. Thrombosis, which occurs following disruption of a pre-existing atherosclerotic plaque, is the immediate cause of most myocardial infarctions and strokes. Therefore factors which regulate the thrombotic response to vascular injury are likely to affect cardiovascular events. The elucidation of these factors is of great clinical importance.

The major focus of our laboratory is to determine the impact of candidate genes on arterial thrombosis and atherosclerosis using in vivo mouse models. We have adapted a photochemical model of arterial injury that elicits occlusive thrombosis for use in the mouse and used it to study mice with genetic alterations of factors involved in the regulation of platelets, fibrinolysis, and coagulation. These studies suggest that pharmacologic manipulation of key regulatory factors in the coagulation and fibrinolytic cascades may be beneficial to patients with atherosclerotic vascular disease.

Recently, we have adapted our mouse models of vascular disease to the study of obesity. Obesity is epidemic in this country and is emerging as a strong independent risk factor for complications of atherosclerosis, such as myocardial infarction and stroke. We found that diet-induced obesity in mice leads to enhanced thrombosis in this model. However, in a genetic mouse model of obesity due to deficiency of leptin, a hormone produced by the fat cell, we found that these obese mice were actually protected from thrombosis. Obese mice lacking the leptin receptor were also protected. Further studies have demonstrated that leptin may be prothrombotic due to its interaction with the leptin receptor on circulating blood elements (platelets or monocytes). Since leptin levels rise with increasing adiposity, this may be one of the factors that leads to the increased risk of cardiovascular disease in obese people. Further studies are exploring signaling mechanisms by which leptin affects vascular disease.