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Cigarette smoke alters lipoprotein & artery wall interaction

Institution: University of California, Los Angeles
Investigator(s): Alan Fogelman, M.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6RT-0006 Award: $472,876
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Second-hand cigarette smoke has been implicated as a cause of increased illness and death. This study will determine the molecular mechanisms by which second-hand cigarette smoke makes “bad cholesterol" (the low density lipoproteins also known as LDL) even worse by promoting their oxidation in the artery wall. This study will also explore the molecular mechanisms by which second-hand cigarette smoke makes the "good cholesterol" (the high density lipoproteins also known as HDL) lose its protective effect and even make it another form of "bad cholesterol”. The net result of these changes induced by second-hand cigarette smoke is to accentuate the inflammatory response that directly causes heart attacks. These studies will provide important scientific evidence to strengthen the public resolve to eliminate second-hand cigarette smoke from public areas in California.

Final Report
Work from this laboratory has shown a key role for oxidized phospholipids derived from lipoproteins in regulating monocyte migration into the artery wall. This Project was directed at determining if LDL from inbred strains of mice and genetically engineered mice exposed to second-hand cigarette smoke was more easily converted to biologically active mildly oxidized LDL by artery wall cells. We also determined the molecular nature of the reactive oxygen species that seed LDL taken from these mice when they were exposed to second hand cigarette smoke. We have demonstrated that the enzymes associated with HDL that are protective against LDL oxidation were modulated by second hand cigarette smoke. We determined that pretreatment of endothelial cells with LDL exposed to second hand cigarette smoke promoted monocyte-endothelial interactions and the HDL exposed to second hand cigarette,smoke failed to inhibit LDL induced monocyte-endothelial interactions. We also found that exposure of mice to second hand cigarette smoke resulted in a decrease in the unoxidized phospholipids in their LDL and an increase in the content of oxidized phospholipids. In humans we found that smokers had the lowest paraoxonase activity of a population of patients with documented coronary heart disease.These data indicate that second hand cigarette smoke renders both HDL and LDL more inflammatory and hence more likely to cause acute coronary syndromes and strokes.
Publications

Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL
Periodical: Journal of Clinical Investigation Index Medicus:
Authors: Ishikawa K, Navab M, Leitinger N, Fogelman AM, Lusis AJ ART
Yr: 1997 Vol: 100 Nbr: Abs: Pg: 1209-1216

Short-term feeding of an atherogenic diet to mice results in a reduction of HDL and paraoxonase that may be mediated by an immune mechanism.
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Hedrick CC, Hassan K, Hough GP, Yoo JH, et al. ART
Yr: 2000 Vol: 20 Nbr: Abs: Pg: 1946-1952

Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: step 1.
Periodical: Journal of Lipid Research Index Medicus:
Authors: Navab M, Hama SY, Cooke CJ, et al. ART
Yr: 2000 Vol: 41 Nbr: Abs: Pg: 1481-1494

Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3.
Periodical: Journal of Lipid Research Index Medicus:
Authors: Navab M, Hama SY, Anantharamaiah GM et al. ART
Yr: 2000 Vol: 41 Nbr: Abs: Pg: 1495-1508