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Cardiovascular consequences of genetic variation at -6/235 in human angiotensinogen using "humanized" gene-targeted mice. Hypertension 2010 Nov;56(5):981-7

Date

09/09/2010

Pubmed ID

20823378

Pubmed Central ID

PMC2959143

DOI

10.1161/HYPERTENSIONAHA.110.157354

Scopus ID

2-s2.0-78149258856   9 Citations

Abstract

Genetic and functional data support a role for angiotensinogen in blood pressure control, and many population studies have suggested that polymorphisms in the angiotensinogen gene contribute to hypertension. Two common haplotypes of the human angiotensinogen gene are -6A/235T and -6G/235M. To study their contributions to blood pressure regulation in a controlled model system, we developed triple-transgenic mice expressing either -6A/235T or -6G/235M human angiotensinogen, expressing either an overexpressed and poorly regulated (REN9) or a tightly regulated (PAC160) human renin, and all carrying a null mutation in the endogenous murine angiotensinogen gene. These humanized mice were then examined for blood pressure differences at baseline and after a high-salt diet, changes in cardiovascular organ weight, and differences in angiotensinogen and renin gene expression. Mice expressing the -6G/235M haplotype on the PAC160 background exhibited increased blood pressure and cardiac hypertrophy at baseline. In contrast, all of the mice with the REN9 background had equivalent baseline blood pressures. On the REN9 background, there was a greater increase in blood pressure in -6A/235T in response to a high-salt diet, providing evidence it may be a susceptibility allele. There were no differences in angiotensinogen expression between haplotypes on either background strain. The data suggest that the impact of angiotensinogen haplotypes on cardiovascular end points may be dependent on renin status and environmental influences, such as dietary sodium. These insights may help explain the discrepancies among observational studies that have examined roles for the -6A/235T and -6G/235M angiotensinogen haplotypes in varied human populations.

Author List

Grobe JL, Dickson ME, Park S, Davis DR, Born EJ, Sigmund CD

Authors

Justin L. Grobe PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Alleles
Angiotensinogen
Animals
Blood Pressure
Genetic Variation
Genotype
Haplotypes
Hypertension
Mice
Mice, Transgenic
Renin
Sodium, Dietary
Telemetry