Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 27, Issue 12, Pages 2699-2706Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.107.153650
Keywords
integrins; TNF alpha; diet; bone marrow transplantation; atherosclerosis; infliximab
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Objective - High-fat, cholesterol-containing diets contribute to hyperlipidemia. Both high-fat diets and hyperlipidemia are associated with chronic inflammatory diseases like atherosclerosis. Integrins, heterodimeric mediators of inflammatory cell recruitment, are not generally thought to be affected by diet. However, high-fat feeding promotes inflammation, atherosclerosis, and death in hyperlipidemic mice with beta 3 integrin deficiency, and treatment of humans from Western populations with oral beta 3 integrin inhibitors increases mortality. The mechanisms responsible for these beta 3 integrinassociated events are unknown. Methods and Results - Here we show that diet-induced death in beta 3 integrin-deficient mice is a TNF alpha-dependent process mediated by bone marrow-derived cells. In 2 different hyperlipidemic models, apoE-null and LDL receptor-null mice, beta 3-replete animals transplanted with beta 3-deficient marrow died with Western-type high-fat feeding whereas beta 3-deficient animals transplanted with beta 3-replete marrow were rescued from diet-induced death. Transplantation with beta 3-deficient marrow also increased atherosclerosis. TNF beta expression was increased in beta 3-deficient macrophages and normalized by either retroviral or adenoviral reconstitution of beta 3 integrin expression. Treatment with the anti-TNF beta antibody infliximab rescued beta 3 integrin-deficient mice from Western diet-induced death, directly implicating TNF alpha in the pathophysiology triggered by diet-induced hyperlipidemia. Conclusions - These findings suggest that macrophage beta 3 integrin, acting through TNF alpha, suppresses inflammation caused by hyperlipidemia attributable to high-fat feeding.
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