The long-term goal is to delineate the mechanisms of the pathogenesis of atherosclerosis and its failure to resolve. It is widely accepted that oxidized low-density lipoprotein (oxLDL) is a critical component in foam cell formation and in the induction of pro-inflammatory cytokine production by vascular endothelial cells and macrophages. However, the molecular basis for maintaining this inflammatory status has not been established. Of interest, the generation of lipid-derived aldehydes in oxLDL retains the bioactivity of oxLDL. In peripheral tissues, the resolution of acute inflammation is accomplished by counter regulatory anti- inflammatory mediators including lipid mediators, such as the recently characterized pro-resolving lipoxins and the novel resolvins (resolution phase interaction products). Although vital for proper host defense against invading pathogens, unresolved inflammation can give rise to a chronic inflammatory phenotype that is observed in many disease states, such as asthma and atherosclerosis. Indeed, lipoxin biosynthesis is decreased in many chronic inflammatory diseases and restoration of pro-resolving circuits with synthetic lipoxins and resolvins reduces inflammation in vivo. The central hypothesis, to be tested in this proposal, is that oxLDL suppresses pro-resolving circuits by preventing the formation of local anti- inflammatory lipid mediators. It follows that local anti-inflammatory lipid mediators should facilitate the clearance of oxLDL, promote the resolution of inflammation and decrease atherogenesis. To test this, the first aim will establish whether oxLDL or its bioactive aldehyde components promote vascular inflammation by inhibiting lipoxin and resolvin biosynthesis. Additional experiments will examine whether restoration of these pathways with lipoxins and resolvins enhances non-phlogistic uptake of oxLDL (i.e., increased clearance without the generation of pro-inflammatory mediators), as assessed by superoxide production (Aim 1) and pro-inflammatory cytokine and lipid mediator generation by macrophages (Aim 2).
Aim 3 will test whether lipoxins and resolvins decrease vascular inflammation and arterial lesions that will be evaluated in apoE-null mice. We will evaluate changes in lesion size, morphology and inflammatory lipid mediator and cytokine production. Overall, results from these studies are aimed to develop a better understanding of the mechanisms by which inflammation is not resolved in atherosclerosis. Elucidation of the role and function of endogenous anti-inflammatory and pro-resolving lipid mediators could form the basis for the development of novel therapeutic interventions and approaches for treating atherosclerosis. ? ? ? ?
| Ho, Karen J; Spite, Matthew; Owens, Christopher D et al. (2010) Aspirin-triggered lipoxin and resolvin E1 modulate vascular smooth muscle phenotype and correlate with peripheral atherosclerosis. Am J Pathol 177:2116-23 |
| Spite, M; Summers, L; Porter, T F et al. (2009) Resolvin D1 controls inflammation initiated by glutathione-lipid conjugates formed during oxidative stress. Br J Pharmacol 158:1062-73 |
| Spite, Matthew; Norling, Lucy V; Summers, Lisa et al. (2009) Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature 461:1287-91 |
