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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2196.)
© 2004 American Heart Association, Inc.

Thrombosis

Inhibition of Endogenous Leptin Protects Mice From Arterial and Venous Thrombosis

Stavros Konstantinides; Katrin Schäfer; Jaap G. Neels; Claudia Dellas; David J. Loskutoff

From The Scripps Research Institute(S.K., J.G.N., C.D., D.J.L.), Department of Cell Biology, Division of Vascular Biology, La Jolla, Calif; and the Department of Cardiology and Pulmonary Medicine (S.K., K.S.), Georg August University of Goettingen, Goettingen, Germany.

Correspondence to David J. Loskutoff, PhD, The Scripps Research Institute, Department of Cell Biology, Division of Vascular Biology, 10550 North Torrey Pines Road, VB-3, La Jolla, CA 92037. E-mail loskutof{at}scripps.edu

Objective— Human obesity is associated with an increased risk for arterial and venous thrombosis and with elevated levels of leptin in the blood. Leptin administration promotes arterial thrombosis in mice, and leptin-deficient ob/ob mice have an attenuated thrombotic response to injury. Thus, endogenous leptin may regulate arterial and venous thrombosis in vivo. Experiments were performed to test this hypothesis.

Methods and Results— A leptin-neutralizing antibody was administered intravenously into wild-type mice 15 minutes before carotid artery injury with ferric chloride. The antibody-treated mice demonstrated prolonged times to thrombotic occlusion and formed unstable, embolizing thrombi. Thus, inhibiting leptin converted the thrombotic phenotype of wild-type mice into one that closely resembled that of ob/ob mice. The effect of leptin inhibition on venous thrombosis and pulmonary embolism was also investigated. Injection of a mixture of collagen and epinephrine into the jugular vein induced fatal pulmonary embolism in >90% of the control wild-type mice but in <40% of their antibody-treated counterparts. Histological analysis revealed that the antibody significantly reduced the number of occlusive thrombi in the pulmonary vessels.

Conclusions— Inhibition of circulating leptin protects against arterial and venous thrombosis in mice and possibly in hyperleptinemic obese individuals.

Human obesity is associated with an increased risk for thrombosis and with elevated leptin. We show that inhibiting circulating leptin protects wild-type mice from arterial and venous thrombosis in vivo. Leptin inhibition may represent a new strategy for reducing the risk of cardiovascular disease in obese hyperleptinemic individuals.

Key Words: carotid arteries • leptin • thrombosis • pulmonary embolism • obesity • mouse models

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