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Effects of environmental tobacco smoke on the artery wall

Institution: University of California, Davis
Investigator(s): John Rutledge, M.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7RT-0070 Award: $449,673
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Environmental tobacco smoke (passive smoking) is strongly associated with disease of the arteries supplying the heart with blood (coronary arteries) and vascular disease of other medium and large arteries of the body, especially in the abdomen and legs. Our previous work showed that a single exposure to environmental tobacco smoke (ETS) increased binding of a cholesterol carrying particle (low density lipoprotein; LDL) to the artery wall. This situation may presage the development of blockage of the artery (atherosclerotic plaque). However, in this earlier work, the specific manner in which ETS mediates this effect on the artery wall was not defined. The overall goal of the current project is to extend our earlier studies to understand the chronic effects of ETS exposure on the walls of arteries. We hypothesize that oxidant stress generated by exposure to ETS modifies the arterial wall to increase LDL binding and vascular stiffening (i.e., hardening of blood vessels), a condition associated with, and possibly causing, atherosclerosis. To test this hypothesis, we will expose mice to ETS and determine the effects on their carotid arteries. Specifically we will: 1) examine the effect of ETS exposure on LDL binding in the artery wall. 2) examine the effect of ETS exposure on vascular stiffening. 3) determine the effect of antioxidants (vitamin E and estrogen) on LDL binding and vascular stiffening in response to ETS. Our studies will investigate mechanisms by which ETS causes vascular disease, an area that has been little studied. Knowledge of the mechanisms of disease progression may rationally guide therapies directed at vascular disease. These therapies could benefit humans who are passively (and often indiscriminately) exposed to environmental tobacco smoke.

Final Report
The major objective during the course of this award was to investigate the actions of environmental tobacco smoke (ETS) on the systemic vascular wall. Specifically we sought to determine how environmental tobacco smoke and its products affected the permeability of the endothelial layer, and how environment tobacco smoke would affect stiffening of blood vessels. Finally we examined the potential attenuating affects of female sex hormones, and specifically estradiol. The major issues addressed were:

1. Does environmental tobacco smoke increase endothelial layer permeability? 2. Does environmental tobacco smoke increase vascular stiffening? 3. Do female sex hormones protect against the vasculotoxic affects of environmental tobacco smoke.

Our studies have shown unequivocally that environmental tobacco smoke injures endothelium and increases endothelial layer permeability. Further arterial stiffening as a result of exposure of rats to environmental tobacco smoke decreases the compliance of the blood vessels and increases the vascular stiffening. Female sex hormones and specifically 17 estradiol had no effect on ameliorating the toxic affects of environmental tobacco smoke on the endothelium and endothelial layer permeability or vascular stiffening. Likewise, antioxidants did not appear to prevent any of the vascular toxic effects of environmental tobacco smoke in our animal model. Recent data from our laboratory indicates that certain reactive aldehydes present in environmental tobacco smoke may be a leading culprit as far as determining vascular disease as a result of tobacco smoking. We will pursue this possibility in the future, in hopes of determining the affect of these reactive aldehydes on the endothelium, platelets, and monocytes.

Our studies have shown that there are consequences related to environmental tobacco smoke and its effect on vascular wall biology. This linkage is clear and the hope for the future is the development of therapies and interventions to prevent this systemic vascular compromise effected by environmental tobacco smoke. Specifically we are hopeful that if reactive aldehydes are found to be important and potent vascular toxic compounds in tobacco smoke that therapeutic agents can be developed which will prevent the effects of reactive aldehydes on the arterial wall.
Publications

17beta-estradiol reduces tumor necrosis factor-alpha-mediated LDL accumulation in the artery wall
Periodical: Journal of Lipid Research Index Medicus:
Authors: Walsh BA, Mullick AE, Walzem RL, Rutledge JC ART
Yr: 1999 Vol: 40 Nbr: 3 Abs: Pg: 387-396

Modified LDL-mediated increases in endothelial layer permeability are attenuated with 17 beta-estradiol
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Gardner G, Banka CL, Roberts KA, Mullick AE, Rutledge JC ART
Yr: 1999 Vol: 19 Nbr: 4 Abs: Pg: 840-846

17 beta-estradiol reduces glycoxidative damage in the artery wall
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Walsh BA, Busch BL, Mullick AE, Reiser KM, Rutledge JC ART
Yr: 1999 Vol: 19 Nbr: 4 Abs: Pg: 840-846

17 beta-estradiol acts separately on the LDL particle and artery wall to reduce LDL accumulation
Periodical: Journal of Lipid Research Index Medicus:
Authors: Walsh BA, Mullick AE, Banka CE, Rutledge JC ART
Yr: 2000 Vol: 41 Nbr: 1 Abs: Pg: 134-141

Smoking and cardiovascular disease
Periodical: Clinics in Chest Medicine Index Medicus:
Authors: Villablanca AC, McDonald JM, Rutledge JC ART
Yr: 2000 Vol: 21 Nbr: 1 Abs: Pg: 159-172