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 expre ssion in both cardiac left ventricle and aorta in various pressure-ove rload rat models and in hypertrophied human heart suggests a common tr anscriptional 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 r egion, H alpha(2)-CAT. Analysis of two homozygous transgenic rat lines revealed (1) parallel tissue-specific regulation of the H alpha(2)-CA T transgene and rat alpha(2) Na,K-ATPase gene and (2) parallel load-in duced 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 mod el of induced pressure overload. Cardiac H alpha(2)-CAT deinduction wa s detected at a systolic pressure greater than or equal to 150 mm Hg a nd correlated with the degree of systolic pressure elevation (r=.82, P <.0001). The data suggest a systolic pressure gradient-dependent coord inate pressure-overload transcriptional response mechanism in the hear t and aorta, with one of its target genes being the alpha(2) Na,K-ATPa se gene in both humans and rats.