Scripps Research Logo

The Curtiss Lab

Research

Innate and Acquired Immunity in Atherosclerosis
Coronary artery disease, the major manifestation of atherosclerosis, is the leading cause of death in the Western world. However, the pathogenesis of atherosclerosis is still poorly understood. At one time, atherosclerosis was thought to be a simple lipid storage disease of large arteries. However, it is now recognized as a chronic and progressive inflammation of the arterial wall. Gene deletion experiments in murine models of atherosclerosis that reduce the inflammatory process also reduce disease severity. Our laboratory is identifying the initiators and mediators of that inflammation that can provide promising avenues for prevention or therapy. Two prominent risk factors, hyperlipidemia and infectious disease, point to innate immune mechanisms as potential contributors to proatherogenic inflammation. The Toll-like receptors (TLR), proinflammatory sensors of pathogens, are potential links between inflammation, infectious disease and atherosclerosis. There is increasing evidence that TLRs also recognize host-derived ligands and this connects TLRs to diseases that have an etiology that is not directly associated with infection. A mechanism for hyperlipidemic initiation of sterile inflammation can be postulated because oxidized lipoproteins or their component oxidized lipids have been identified as TLR ligands. Moreover, infectious agents are correlated with atherosclerosis risk. TLR4 activation is relevant to the inflammation of atherosclerosis in mice and humans. In addition, we have identified a role for TLR2 in atherosclerosis in low density lipoprotein receptor-deficient (LDLr-/-) mice. Proatherogenic TLR2 responses to unknown endogenous or unknown endemic exogenous agonists are mediated by non-bone marrow-derived cells, which can include endothelial cells, adventitial fibroblasts and vascular smooth muscle cells. This is in contrast to the proatherogenic TLR2 response to defined synthetic exogenous agonists that is mediated at least in part by bone marrow-derived cells, which include lymphocytes, monocytes/macrophages, NK cells and dendritic cells. Thus, by different cellular pathways TLR2-mediated cell activation in response to endogenous and exogenous agents is proatherogenic in hyperlipidemic mice.

Research image

Severe Abdominal Atherosclerosis
Phospholipid transfer protein (PLTP) remodels high density lipoproteins (HDL) into large and small particles. It also mediates the dissociation of lipid-poor or lipid-free apo A-I from HDL. Because remodeling is enhanced markedly in triglyceride-enriched HDL, we wished to define the mechanism of the remodeling of HDL by PLTP and determine why it is enhanced in triglyceride-enriched HDL. Homogeneous populations of spherical reconstituted HDL containing apoA-I and either cholesteryl esters or cholesteryl esters and triglycerides in their core were used. After exposure to PLTP all of the triglyceride-rHDL, but only a proportion of the cholesteryl ester-rHDL, were coverted into large (diameter 11.3 nm) and small (diameter 7.7 nm) lipoprotein particles. The composition of the large particles indicated that they were derived from a fusion product. Spectroscopic studies indicated that the apoA-I in triglyceride-rHDL was less stable than the apoA-I in cholesteryl ester-rDHL. These studies revealed that PLTP-mediates rHDL fusion and that the fusion product rearranges by two independent processes into small and large lipoprotein particles and that the more rapid remodeling of triglyceride-rHDL by PLTP may be due to the destabilization of apoA-I. 

Research image

___________

Home
___________

Research
___________

Personnel
___________

Selected Publications
___________

Links
___________

Alumni
___________

Contacts
___________