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Articles in PresS, published online ahead of print October 8, 2002
Physiol Genomics, 10.1152/physiolgenomics.00076.2002
Submitted on June 18, 2002
Accepted on October 2, 2002
1 Molecular Biology, University of Iowa, Iowa City, IA, USA
2 Internal Medicine, University of Iowa, Iowa City, IA, USA
3 OB/GYN, University of Iowa, Iowa City, IA, USA
4 Internal Medicine, University of Iowa, Iowa City, IA, USA; Physiology & Biophysics, University of Iowa, Iowa City, IA, USA
* To whom correspondence should be addressed. E-mail: curt-sigmund{at}uiowa.edu.
Angiotensinogen was the first gene to be genetically linked to hypertension in humans. Analysis of the gene sequence identified a number of polymorphisms, several of which were reported associated with increased blood pressure (BP) or other cardiovascular diseases. One haplotype of the human angiotensinogen (hAGT) gene consisting of an allele at the-6 (A vs G) position in the promoter, and in the sequence encoding amino acid 235 (Thr vs Met) attracted the most attention and has been the subject of numerous association studies. In this report, we addressed the physiological relevance of alleles at these two positions using an experimental mouse model system. Transgenic mice were generated by targeting each haplotype (GM, AT) as a single copy transgene to the mouse hypoxantine phosphoribosyl transferase locus, allowing direct comparison of the two transgenes in vivo. Our results indicate that both transgenes exhibit the same transcriptional activity and produce similar levels of hAGT protein in the plasma of the transgenic mice. Blood pressure analysis was performed in double transgenic mice generated by breeding each hAGT line to mice expressing a human renin gene. A small but significant increase in blood pressure and relative heart weight was demonstrated by mice carrying the GM haplotype. Moreover, compensatory down-regulation of endogenous renin expression was more pronounced in mice containing the GM variant. Our findings suggest that the AT and GM haplotypes of the hAGT gene have no effect on gene expression, but may affect the cardiovascular system and the regulation of BP differently.
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