Characterizing the role of endothelin-1 in the progression of cardiac hypertrophy in aryl hydrocarbon receptor (AhR) null mice.
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor characterized to play a role in detection and adaptation to environmental stimuli. Genetic deletion of AhR results in hypertension, and cardiac hypertrophy and fibrosis, associated with elevated plasma angiotensin II (Ang II) and endothelin-1 (ET-1), thus AhR appears to contribute to cardiovascular homeostasis. In these studies, we tested the hypothesis that ET-1 mediates cardiovascular pathology in AhR null mice via ETA receptor activation. First, we determine the time courses of cardiac hypertrophy, and of plasma and tissue ET-1 expression in AhR wildtype and null mice. AhR null mice exhibited increases in heart-to-body weight ratio and age-related expression of cardiac hypertrophy markers, beta-myosin heavy chain (beta-MHC), and atrial natriuretic factor (ANF), which were significant at 2 months. Similarly, plasma and tissue ET-1 expression was significantly elevated at 2 months and increased further with age. Second, AhR null mice were treated with ETA receptor antagonist, BQ-123 (100 nmol/kg/day), for 7, 28, or 58 days and blood pressure, cardiac fibrosis, and cardiac hypertrophy assessed, respectively. BQ-123 for 7 days significantly reduced mean arterial pressure in conscious, catheterized mice. BQ-123 for 28 days significantly reduced the histological appearance of cardiac fibrosis. Treatment for 58 days significantly reduced cardiac mass, assessed by heart weight, echocardiography, and beta-MHC and ANF expression; and reduced cardiac fibrosis as determined by osteopontin and collagen I mRNA expression. These findings establish ET-1 and the ETA receptor as primary determinants of hypertension and cardiac pathology in AhR null mice.
Lund
Amie K
AK
College of Pharmacy, School of Medicine, Department of Pediatrics, University Hospital, University of New Mexico, Albuquerque, New Mexico 87131, USA.
Goens
M Beth
MB
Nuñez
Bethany A
BA
Walker
Mary K
MK
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D004452:Echocardiography; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D005355:Fibrosis / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000502:physiology; D009929:Organ Size / Q000235:genetics / Q000502:physiology; D010456:Peptides, Cyclic / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D044022:Receptor, Endothelin A / Q000502:physiology; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D018336:Receptors, Aryl Hydrocarbon; D000804:Angiotensin II; C072247:cyclo(Trp-Asp-Pro-Val-Leu)