Elevated pai-1 and tissue factor gene expression in obese mice: a possible mechanism for the increased risk for cardiovascular disease associated with obesity

Elevated levels of plasma PAI-1 are observed in human obesity and may contribute to fibrin deposition and cardiovascular risk associated with this condition. Although plasma coagulation factor VII also is elevated in obese individuals, there is surprisingly little information available about the levels of tissue factor (TF), the cellular receptor for factor VII and the primary initiator of the coagulation cascade. We previously demonstrated that genetically obese (ob/ob) mice are a useful model of human obesity since plasma PAI-1 also is significantly elevated in these animals. This increase seems to result from increased expression of PAI-1 by the adipose tissue itself in response to TNF-a, TGF- and insulin. Based on these observations, we hypothesize that TF may also be increased, and that a concurrent increase in TF and PAI-1 may promote the prothombotic state in obesity. To test this possibility, we analyzed TF gene expression in tissues from lean and obese mice. TF mRNA expression was elevated in brain, lung, kidney, heart, liver and adipose tissue of the ob/ob mouse compared to its lean counterpart. In situ hybridization analysis, revealed increased cellular expression of TF in bronchiolar epithelial cells of the lung, in myocytes in the heart, and in adventitial cells lining blood vessels of the obese mouse. In the adipose tissue, TF mRNA expression was increased in adipocytes and in unidentified cells. Insulin is systemically elevated in the plasma of ob/ob mice, and administration of insulin to lean mice, increased TF expression in the kidney, brain, heart and lung, but only minimally in the adipose tissue. TGF- is elevated locally in the adipose tissues of obese mice, and administration of TGF- to normal CB6 mice increased TF mRNA expression in the adipocytes within the adipose tissue. Since insulin and TGF- also increase PAI-1, these agents may promote increased cardiovascular risk and other pathologies associated with obesity.