| The heterodimeric integrin αvβ3 is an important sensor of the extracellular environment. Down-stream signaling fromαvβ3 influences many cellular processes including proliferation, migration, inflammation and survival. These processes are central to the progression of atherosclerotic lesions in the vessel wall. In the atherogenic apolipoprotein E (apoE) and low-density lipoprotein receptor null backgrounds, β3 null mice are prone to atherosclerosis and die spontaneously of sterile lung inflammation when fed a high-fat Western style diet. Expression levels of inflammatory proteins CD36, CD40L and CD40 are elevated in vascular smooth muscle cells from β3 integrin null mice. This inflammatory state can be corrected by restoration of β3 expression using a retrovirus. Atherosclerosis and spontaneous death data from β3 and apoE double null mice reveals a new connection between fatty acid metabolism, the β3 integrin and inflammation. In light of these data, control of αvβ3 expression in the vessel wall should reveal important insights into the factors that control inflammation and lesion progression. Palmitic acid, a saturated fatty acid commonly found in human diets, decreases β3 integrin expression levels in primary porcine vascular smooth muscle cells. This response is dose dependent and maximal at 24 hours of palmitate exposure. Palmitate treatment does not induce apoptosis as detectable by propidium iodide staining or fluorescent DNA end labeling. Downregulation of the β3 integrin message occurs, in part, through mRNA destabilization. These data indicate that palmitic acid has a role in regulating an anti-inflammatory protein, β3 integrin, in vascular smooth muscle cells. Elucidation of the mechanism underlying this phenomenon may reveal a novel paradigm for the induction of inflammation by palmitate in smooth muscle cells. This project focuses on the effect of fatty acid metabolism on the expression of β3 integrin in vascular smooth muscle cells. |
