Science Inventory

Rat Models of Cardiovascular Disease Demonstrate Distinctive Pulmonary Gene Expressions for Vascular Response Genes: Impact of Ozone Exposure


WARD, W. O., M. SCHLADWEILER, A. D. LEDBETTER, AND U. P. KODAVANTI. Rat Models of Cardiovascular Disease Demonstrate Distinctive Pulmonary Gene Expressions for Vascular Response Genes: Impact of Ozone Exposure. Presented at Annual Society of Toxicology meeting, Baltimore, MD, March 15 - 19, 2009.


This abstract characterizes the baseline pulmonary complications as determined by expression analysis associated with genetic cardiovascular disease and shows that vascular response genes are differentially altered by ozone. This is a part of large susceptibility project in the lab.


Comparative gene expression profiling of multiple tissues from rat strains with genetic predisposition to diverse cardiovascular diseases (CVD) can help decode the transcriptional program that governs organ-specific functions. We examined expressions of CVD genes in the lungs of rat models at baseline and following ozone exposure to reveal potential mechanisms of disease etiology and susceptibility to ozone. Gene lists that represent genes associated with heart failure, obesity, hypertension and stroke were compiled from the current literature. Each of these four gene lists was distinct with a maximum overlap of genes between any two lists of 19%. Using rat 230A Affymetrix GeneChips, lung-tissue gene expression was measured for male 12-14 week old Wistar Kyoto (WKY, healthy), Spontaneously Hypertensive (SH), Stroke-Prone SH (SHRSP), Heart Failure SH (SHHF) and Diabetic (JCR) rats immediately following air or 1.0 ppm ozone exposure for 4 hrs. Principal component analysis for each of the gene lists identified clusters of gene expression for each of the rat strains exposed to air. For hypertension genes there were three clusters with similar gene expression response: 1) JCR; 2) WKY, SHR, and SHRSP; and 3) SHHF strain. Among the hypertension genes, genes regulating vasoconstriction were induced in the lungs of JCR but down-regulated in the other strains. Genes regulating vasodilation were suppressed in JCR but primarily upregulated in the other strains. For heart failure and stroke genes there were three clusters: 1) JCR; 2) WKY; and 3) SHR, SHHF and SHRSP strains. For obesity genes, there were three clusters: 1) JCR; 2) SHR, SHRSP, and WKY; and 3) SHHF strain. The similarity of expression response among the SHR, SHRSP, and WKY rat strains is partially attributable to the known similarity among their genomes. Ozone caused minimal pulmonary response (few genes changed) in JCR but marked response in other strains (WKY>SHRSP>SHR>SHHF>>JCR). Based on a significance analysis of functional categories, heart failure genes appeared most affected by ozone in JCR, SHRSP and WKY strains. By this same analysis, stroke genes were altered in the SHR strain. Our study demonstrates how pulmonary expression patterns are influenced by cardiovascular disease and provides insights into the mechanisms of ozone susceptibility differences among disease models. (Does not reflect US EPA policy.)

Record Details:

Product Published Date: 03/16/2009
Record Last Revised: 04/15/2009
OMB Category: Other
Record ID: 201563