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Pathophysiologic Mechanisms of Obesity-Associated Cardiovascular Disease

F. Samad, M. Pandey

Obesity is associated with a cluster of abnormalities, including insulin resistance, hyperinsulinemia, hypertension, and elevated levels of proinflammatory and prothrombotic proteins. Although these changes may increase the risk for cardiovascular disease, the underlying molecular mechanisms have not been defined. Our primary hypothesis is that the expanded adipose tissue in obesity acts as a proinflammatory and prothrombotic endocrine organ, directly contributing to and promoting the increased risk for cardiovascular disease. This hypothesis is based on observations by us and others that products of the adipose tissue include molecules such as TNF-a, IL-6, leptin, plasminogen activator inhibitor-1 (PAI-1), tissue factor (TF), and transforming growth factor-b, all of which are potent risk factors for cardiovascular disease and are markedly upregulated in obesity.

TF is the major cellular initiator of the coagulation cascade, and previously we showed that its expression is elevated in the adipose tissues of genetically obese (ob/ob) mice. In related studies, we used obese ob/ob and db/db mice to determine whether TF also was elevated in other tissues of obese mice. Because of the strong correlation between obesity and hyperinsulinemia, we also examined whether these effects were mediated by insulin.

We found that TF mRNA also was significantly elevated in the brain, lung, kidney, liver, and heart of both ob/ob and db/db mice. Moreover, insulin could contribute to the increase in TF gene expression in some of these tissues. The coordinated increase in the expression of procoagulant genes such as those for TF and PAI-1 in obesity would be expected to increase coagulation and impair fibrinolysis, thereby promoting a state that favors thrombosis.

The proinflammatory cytokine TNF-a also is chronically elevated in obesity and has been implicated in the insulin resistance and elevated expression of PAI-1 associated with obesity. However, little is known about the receptors for TNF-a that mediate expression of PAI-1 in obesity. Using ob/ob mice genetically deficient in the TNF-a receptors p55 and p75, we examined the role played by p55 and p75 in mediating the expression of PAI-1. We found that in ob/ob mice both p55 and p75 appear to act cooperatively to induce PAI-1 mRNA in most tissues, including adipose tissue, heart, kidney, and liver. These results indicate a unique and unexpected role for p75 in the induction of PAI-1 in obesity.

PUBLICATIONS

Samad, F., Pandey, M., Loskutoff, D.J. Regulation of tissue factor gene expression in obesity. Blood, 98:3353, 2001.