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ApoE related effect of smoking in cardiovascular disease

Institution: Children's Hospital Oakland Research Institute
Investigator(s): Vasanthy Narayanaswami, Ph.D.
Award Cycle: 2008 (Cycle 17) Grant #: 17RT-0165H Award: $678,561
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards

Initial Award Abstract
Heart disease and stroke are the #1 and #3 killers, respectively, in North America, with about 50% of all strokes in the US attributable to cigarette smoking. It is generally accepted that elevated plasma levels of low density lipoprotein cholesterol are risk factors for cardiovascular and cerebrovascular disease. However, the effect of secondhand smoke exposure on plasma lipoprotein status is not known. The objective of our study is to investigate the effect of secondhand smoke exposure on the role of an anti-atherogenic protein called apolipoprotein E (apoE) that plays a critical role in cholesterol transport in the vascular and central nervous system. It serves as a ligand for binding cell surface lipoprotein receptors. Cellular uptake of the lipoproteins enables lowering of plasma cholesterol and triglycerides levels. Therefore any process that “tampers” with the recognition of apoE with receptors may contribute towards build-up of plasma lipids.

One of the processes that can alter the recognition of apoE by receptors is oxidative modification by a highly reactive molecule called acrolein that is present as a component of tobacco smoke or may be generated in situ due to smoking itself. Chemically, it displays high reactivity with protein side-chains (such as lysines). In the case of apoE, lysines are important for binding lipoproteins to the receptors. We propose that chemical modification of apoE due to secondhand smoke exposure will impair its functional ability to lower plasma cholesterol levels.

We detected acrolein-modified apoE in plasma of smokers in a small sample volume and in rats exposed to secondhand smoke under conditions that simulate passive smoke exposure in humans. It is not known if this acrolein originated directly from tobacco smoke or indirectly due to enhanced cellular oxidative stress under smoke-exposed conditions. Regardless of the source, our preliminary studies show that acrolein modification of apoE decreases its ability to interact with receptors. We will examine an existing tissue archive of plasma of smokers, passive smokers and non-smokers for the levels of acrolein-modified apoE, and correlate this information with the plasma levels of lipids. We will carry out a similar analysis with rats exposed to tobacco smoke. In parallel, we will examine the ability of oxidatively modified apoE to mediate binding and uptake of lipoproteins localized on endothelial cells isolated from human brain microvasculature. These cells are of direct interest since they are an important component of the barrier that separates the vascular from the central nervous system and little is known regarding the role of oxidative stress in cholesterol metabolism at this neurovascular junction. Lastly, we will investigate the effect of oxidative modification on the structure and function of recombinant human apoE.

The implication of our proposal is that long-term and sustained secondhand smoke exposure is likely to have a cumulative detrimental effect on apoE function and may predispose individuals towards developing heart disease and stroke. The outcome of the present study will significantly advance our knowledge of the role of apoE-related oxidative stress in cardiovascular and cerebrovascular disease. It will lay the groundwork for future studies aimed at monitoring the risk for children exposed to passive smoke and other environmental oxidative stressors. When combined with poor lifestyle and dietary habits, we envisage that the additional factor of secondhand smoke exposure may further predispose children towards developing a pro-atherogenic plasma lipid profile.

Anti-Parallel beta sheet - A signature structure of the oligometric amyloid-beta peptide.
Periodical: Biochemical Journal Index Medicus:
Authors: Cerf, E; Sarroukh, R; Tamamizu-Kato, S; et al ART
Yr: 2009 Vol: Nbr: Abs: Pg:

A new HDL mimetic peptide that stimulates cellular cholesterol efflux with high efficiency greatly reduces atherosclerosis in mice.
Periodical: Journal of Lipid Research Index Medicus:
Authors: Bielicki, JK; Zhang H; Cortez, Y; Zheng, Y; Narayanaswami, V; Patel, A; Johansson, J; Azha ART
Yr: 2010 Vol: Nbr: Abs: Pg:

Pyrene fluorescence analysis offers new insights into the conformation of the lipoprotein-binding domain of human apolipoprotein E.
Periodical: Biochemistry Index Medicus:
Authors: Patel, AB; Khumsupan, P; Narayanaswami, V; ART
Yr: 2010 Vol: 49 Nbr: Abs: Pg: 1766-1775

Full -length apolipoprotein E protects against the neurotoxicity of an apoE-related peptide.
Periodical: Brain Research Index Medicus:
Authors: Crutcher, KA; Lilley, HN; Anthony, SR; Zhou, W; Narayanaswami, V ART
Yr: 2010 Vol: Nbr: 1306 Abs: Pg: 106-115

The helix bundle: a reversible lipid binding motif.
Periodical: Comparative Biochemistry and Physiology A Molecular & Integrative Physiology Index Medicus:
Authors: Narayanaswami, V; Kiss, RS; Weers, PM ART
Yr: 2010 Vol: Nbr: 155 Abs: Pg: 123-133