There is a growing body of evidence that hypercholes-terolemia renders microvascular endothelium more susceptible to the deleterious consequences of inflammatory stimuli such as I/R. I/R per se is known to elicit an oxidative stress and promote leukocyte adhesion in postcapillary venules. Both of these responses are exacerbated during hypercholesterolemia and can be blocked by pretreatment with either SOD or a xanthine oxidase inhibitor (allopuri-nol). This suggests that O2- generated from xanthine oxidase mediates the leukocyte accumulation elicited by hypercholesterolemic tissues exposed to I/R. Hypercholes-terolemia also enhances the P-selectin upregulation that is normally elicited by I/R. In addition, the hypercholes-terolemia-induced exacerbation of inflammation is seen when tissues are challenged with either lipid mediators (leukotriene B4 and PAF) or cytokines such as TNF-a.
It has also been shown that hypercholesterolemia exacerbates the protein extravasation in venules induced by various inflammatory stimuli, and that this may be due to the enhanced leukocyte recruitment. However, administration of oxLDL in the local arterial supply of tissues exposed to I/R promotes leukocyte adhesion and emigration, without an accompanying increase in albumin extravasation. Although oxLDL is able to induce most of the microvascular alterations observed during diet-induced hypercholesterolemia, the underlying mechanisms appear to differ between these two forms of microvascular dysfunction.
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