Cardiac hypertrophy in aryl hydrocarbon receptor null mice is correlated with elevated angiotensin II, endothelin-1, and mean arterial blood pressure.
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.
Lund
Amie K
AK
College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA.
Goens
M Beth
MB
Kanagy
Nancy L
NL
Walker
Mary K
MK
D000804:Angiotensin II / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D015415:Biomarkers; D002216:Captopril / Q000627:therapeutic use; D004195:Disease Models, Animal; D004452:Echocardiography; D019332:Endothelin-1 / Q000097:blood; D005819:Genetic Markers; D006352:Heart Ventricles / Q000187:drug effects; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000235:genetics; D024723:Ventricular Myosins / Q000187:drug effects / Q000235:genetics
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D015415:Biomarkers; D019332:Endothelin-1; D005819:Genetic Markers; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D000804:Angiotensin II; D002216:Captopril; D024723:Ventricular Myosins