Abstract 271: Thrombospondin-1 Plays a Direct Role in Leptin-Induced Atherosclerosis

Hyperleptinemia, characteristic of diabetes and a hallmark feature of obesity, contributes to the increased risk of atherosclerotic complications. We recently reported that leptin has a direct regulatory effect on the expression of a potent proatherogenic and antiangiogenic matricellular protein thrombospondin-1 (TSP-1) in vitro and in vivo . While leptin and TSP-1 are independently linked to atherosclerosis, a potential cross-talk in vivo remains unknown. The present study is the first evidence that TSP-1 plays a direct role in leptin-induced atherosclerosis. Briefly ApoE -/- and TSP-1 -/- /ApoE -/- double knockout (dKO) mice at 17 wks of age, on regular chow diet, were injected i.p. with murine recombinant leptin (5μg/g body weight) or PBS (vehicle control) once daily for 3 wks and mice were sacrificed at 20 wks of age. Using en face atherosclerotic lesion assay shown by Oil red O staining, we demonstrated that while leptin in vivo significantly increased (2.5-fold) lesion area in the aortic walls of ApoE -/- mice, TSP-1 -/- /ApoE -/- dKO mice developed relatively fewer lesions in response to exogenous leptin. Using high-frequency ultrasound imaging we found that in ApoE -/- mice leptin significantly decreased diameter of transaortic arch, ascending and descending aorta (p < 0.01), while TSP-1 -/- /ApoE -/- dKO mice were completely protected against this leptin-induced reduction in aortic vessel diameter. Ultrasound imaging of common carotid artery further revealed that leptin-treated TSP-1 -/- /ApoE -/- dKO mice were protected against development of vascular lesions while leptin-treated ApoE -/- mice showed more pronounced lesions and a significant reduction in carotid artery internal diameter (p ≤ 0.02). Finally, while leptin in vivo significantly increased plasma cholesterol (~40%) and triglyceride (2.5 fold) levels in ApoE -/- mice, this leptin-induced increase in plasma lipid levels was attenuated in TSP-1 -/- /ApoE -/- dKO mice. Together, our results suggest that knockout of TSP-1 protects ApoE -/- mice against leptin-induced atherosclerosis in vivo , underscoring a novel role of TSP-1 in hyperleptinemia-induced macrovascular complications.