Pressure-overload deinduction of human alpha 2 Na,K-ATPase gene expression in transgenic rats.
The early and sustained deinduction of alpha 2 Na,K-ATPase gene expression in both cardiac left ventricle and aorta in various pressure-overload rat models and in hypertrophied human heart suggests a common transcriptional pressure response mechanism to pressure overload in both rats and humans. To test this hypothesis, we developed transgenic rat lines expressing the chloramphenicol acetyltransferase reporter gene regulated by the human alpha 2 Na,K-ATPase (-798 to +67) regulatory region, H alpha 2-CAT. Analysis of two homozygous transgenic rat lines revealed (1) parallel tissue-specific regulation of the H alpha 2-CAT transgene and rat alpha 2 Na,K-ATPase gene and (2) parallel load-induced deinduction of both cardiac and vascular (aortic) H alpha 2-CAT transgene and rat alpha 2 Na,K-ATPase gene expression in a 3-day model of induced pressure overload. Cardiac H alpha 2-CAT deinduction was detected at a systolic pressure greater than or equal to 150 mm Hg and correlated with the degree of systolic pressure elevation (r = .82, P < .0001). The data suggest a systolic pressure gradient-dependent coordinate pressure-overload transcriptional response mechanism in the heart and aorta, with one of its target genes being the alpha 2 Na,K-ATPase gene in both humans and rats.
Ruiz-Opazo
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Section of Molecular Genetics, Whitaker Cardiovascular Institute, Evans Department of Medicine, Boston (Mass) University School of Medicine 02118, USA.
Xiang
X H
XH
Herrera
V L
VL
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase; D015536:Down-Regulation / Q000235:genetics*; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics* / Q000378:metabolism*; D013312:Stress, Physiological / Q000235:genetics*
D000804:Angiotensin II; D015500:Chloramphenicol O-Acetyltransferase; D000254:Sodium-Potassium-Exchanging ATPase