O236	Differential effects of exogenous and endogenous leptin on the growth of spontaneous atherosclerotic lesions in female and male apolipoprotein E knockout mice.
K.Schäfer, B.Schumann, R.Glückermann, S.Konstantinides
Department of Cardiology and Pulmonary Medicine, University of Goettingen, Göttingen, DE.

The adipokine leptin has been shown to promote arterial thrombosis and neointimal growth after vascular injury in wild-type and obese (ob/ob) mice. However, its effects on atherosclerosis development are unknown. In the present study, we used two different approaches to address this issue. In the first model (exogenous hyperleptinemia), chow-fed male and female apoE-knockout mice (apoE-/-; 10-14 weeks old) were treated with recombinant murine leptin at various dosages (0.04, 0.3, or 0.6 mg/kg BW daily), or with PBS (controls), using subcutaneous osmotic pumps (12 mice per group). Mean circulating leptin levels were higher in female compared to male mice both in the control (1.4±0.5 vs. 0.7±0.2 ng/mL) and the high-dose leptin group (9.4±2.2 vs. 4.4±1.8 ng/mL). After treatment for 8 weeks, atherosclerotic lesions were analyzed on serial sections through the aortic root. Plaques from control and leptin-treated mice of both sexes strongly expressed leptin receptor mRNA and protein. Interestingly however, plaque area was dose-dependently reduced by leptin treatment only in female mice (P=0.008 for highest dose compared to controls), while, in their male counterparts, leptin treatment even at the highest dosage had no effect. Of note, exogenous leptin did not affect plasma cholesterol levels, which were moderately elevated (201±24 mg/dL) in chow-fed apoE-/- mice of both genders. In the second model, endogenous hyperleptinemia (plasma levels, 11.2±2.1 ng/mL; P=n.s. vs. high-dose leptin treatment) was induced in apoE-/- mice by atherogenic high-fat diet (HFD) for 8 weeks. As expected, this diet increased plasma cholesterol levels to 833±97 mg/dL (P<0.001 vs. chow-fed mice). Atherosclerotic lesion size was significantly larger compared to chow-fed animals (P<0.001), but, in contrast to the findings in the previous model, did not differ between male and female mice. Moreover, additional treatment of these animals with high-dose (0.6 mg/kg) leptin tended to further increase aortic plaque area, particularly in the female mice (P=0.05 vs. HFD alone). These results suggest that leptin treatment may exert gender-specific protective effects on atherosclerotic lesion growth, which are, however, abolished or even reversed in diet-induced hyperleptinemia and hypercholesterolemia. Further studies are being performed to determine how diet and other environmental factors may influence the effects of leptin on vascular homeostasis.

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