Cardiac hypertrophy in aryl hydrocarbon receptor null mice is correlated with elevated angiotensin II, endothelin-1, and mean arterial blood pressure.

Abstract:

:The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates toxicity of xenobiotics, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. Genetic deletion of the AhR leads to cardiac hypertrophy, suggesting a role for the AhR in cardiovascular physiology and disease; however, the pathways involved in the development of cardiac hypertrophy have not been determined. Thus, we investigated the role of (1) pressure overload using indwelling catheters and (2) vasoactive peptides endothelin-1 (ET-1) and angiotensin II (Ang II), assessed by RIA, in the progression of cardiac hypertrophy in AhR-null mice. Histochemical analysis, expression of cardiac hypertrophy marker genes, and echocardiography were used to assess the degree of cardiac hypertrophy. AhR-null mice developed elevated mean arterial pressures (MAP) by 5 months, which was associated with a two- and ninefold increase in plasma ET-1 and Ang II, respectively, compared to wild-type. Captopril-treatment (4 mg/kg) of AhR-null mice from 2 to 5 months of age significantly decreased MAP and plasma Ang II, but did not affect ET-1. Further, captopril improved cardiac function and reduced cardiac hypertrophy as evidenced by reduction in left ventricle mass, left ventricle internal dimension, and molecular cardiac hypertrophy markers. Captopril also decreased fibrosis of the heart and kidney. These findings show that pressure overload is associated with elevated ET-1 and hypertrophic growth of the heart and that cardiac hypertrophy is mediated, in part, by Ang II.

journal_name

Toxicol Appl Pharmacol

authors

Lund AK,Goens MB,Kanagy NL,Walker MK

doi

10.1016/j.taap.2003.08.008

subject

Has Abstract

pub_date

2003-12-01 00:00:00

pages

177-87

issue

2

eissn

0041-008X

issn

1096-0333

pii

S0041008X03004149

journal_volume

193

pub_type

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