More than one billion people worldwide smoke cigarettes. In addition, it is estimated that there are at least 125 million children and non-smoking adults exposed to secondhand smoke in the U.S. alone. Both active and passive exposure to tobacco smoke (TS) is a major risk factor for cardiovascular disease, including hypertension. Cardiovascular injury induced by TS is mediated, in part, by oxidative stress. While TS is a source of free radicals, it also activates endogenous pathways that generate reactive oxygen species (ROS). One enzyme that is a significant source of ROS and is highly induced in the vasculature by chemicals in TS is cytochrome P4501A1 (CYP1A1). While the contribution of CYP1A1 induction to TS-induced cancer has been extensively studied, there have been no studies investigating the contribution of endothelial CYP1A1 induction to TS-induced vascular dysfunction and altered hemodynamics in vivo. Since TS is a highly complex mixture of chemicals, it is difficult to dissect out the contribution or mechanism of any single downstream pathway. To tackle this challenge we have developed a novel transgenic mouse model that allows for conditional over expression of CYP1A1 in the vasculature to address the innovative proposal that CYP1A1 induction is an independent risk factor for vascular dysfunction and hypertension in vivo. Our new preliminary data show that over expression of CYP1A1 solely in endothelial cells induces hypertension and exposure of mice to an individual chemical in TS may lead to activation of the renin-angiotensin system (RAS), a major regulator of vascular function and blood pressure. Thus, we will test the hypothesis that over expression of CYP1A1 in vascular endothelium significantly increases ROS which induce vascular dysfunction and angiotensin (Ang) II-dependent hypertension. This hypothesis will be tested in two aims where we will (Aim 1) establish the contribution of ROS and Ang II to hypertension induced by CYP1A1 over expression in vascular endothelium by multiple measurements of ROS and by measuring blood pressure with radiotelemetry 1 treatments with antioxidants or an Ang II receptor blocker, and (Aim 2) elucidate the mechanism by which endothelial CYP1A1 over expression disrupts vascular function independently of increases in blood pressure by evaluating endothelial-dependent dilation and constriction in mesenteric arteries ex vivo prior to increases in blood pressure. This proposal will establish the degree to which induction of endothelial CYP1A1 is an independent mediator of vascular dysfunction and altered hemodynamics in vivo and will elucidate its potential as a drug target to prevent vascular disease induced by both active and passive TS exposure.

Public Health Relevance

Individuals that smoke cigarettes or are exposed to secondhand smoke are at much higher risk for developing cardiovascular disease, including coronary heart disease, peripheral vascular disease, and stroke. Tobacco smoke contains chemicals which increase the expression of cytochrome P4501A1 in the cells that line the blood vessels. This enzyme is a significant source of reactive oxygen species, which can cause vascular injury. Thus, to establish the degree to which induction of this enzyme mediates vascular injury and to elucidate its potential as a drug target to prevent vascular disease induced by exposure to tobacco smoke, we developed a novel transgenic mouse model that allows for cell type-specific over expression of CYP1A1.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL107133-02
Application #
8291248
Study Section
Special Emphasis Panel (ZRG1-VH-B (02))
Program Officer
Gao, Yunling
Project Start
2011-07-01
Project End
2012-08-31
Budget Start
2012-07-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$188,750
Indirect Cost
$63,750
Name
University of New Mexico Health Sciences Center
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Agbor, Larry N; Wiest, Elani F; Rothe, Michael et al. (2014) Role of CYP1A1 in modulating the vascular and blood pressure benefits of omega-3 polyunsaturated fatty acids. J Pharmacol Exp Ther 351:688-98