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Human AGTR1 ExpressionGenetics Influence Hypertension and Heart Disease
The renin-angiotensin system (RAS) increases blood pressure by activating AT1R, which occurs in numbers determined by its gene expression.
The human angiotensin II type 1 receptor gene (AGTR1) is expressed in the adrenal glands, liver, kidneys, smooth muscle (Elton and Martin 2003), brain (Hohle et al 1995), and adipose (de Gasparo 2000). There are complex mechanisms that regulate both the expression and activity of the receptor. It is possible that the number of receptors available on the cell surface may influence the effects of the RAS, including blood pressure and cardiovascular disease. Regulation of Gene ExpressionTranscriptional regulation is at the level of RNA production. This can be influenced by mutations in the DNA sequence that slow down or speed up the transcriptional machinery. Relatively little work has been done to determine the transcriptional regulation of AGTR1. However, it is known that there are mutations in the promoter region of the gene, where the transcription machinery binds, that may influence transcription factor binding and thus the rate of transcription. If post-transcriptional processes are equal, individuals with particular mutations may have more AT1R being produced on a constant basis. Much more is known about the regulation of the protein than of its gene. Regulation of AT1R LevelsThe regulation of AT1R levels is somewhat dependent on the stability of its mRNA and the recycling of the receptor to the cell surface after binding to angiotensin II (Ang II). The receptor is down-regulated by the expression of Ang II, which is tied to the gene expression of angiotensinogen (AGT) (Kaschina and Unger 2003). This complicates the influence of gene expression on blood pressure, and may even offer a balance if one gene is over-expressed. Hyperinsulemia has been associated with the physiological characteristics of hypertension, such as reduced sodium excretion from the kidneys. In the smooth muscle cells of blood vessels, Nickenig’s group in Germany (Nickenig et al 1998) found that insulin affects AT1R gene expression by post-transcriptional mechanisms. Thyroid hormone has also been found to down-regulate vascular AT1R at both the transcriptional and post-transcriptional levels (Fukuyama et al 2003), showing an ability to reverse the effects of the RAS. AT1R and Cardiovascular DiseaseThe incidence of cardiovascular disease increases in postmenopausal women, which implies that estrogens play a role in the development of disease. Nickenig et al (2000) has shown that estrogen, specifically 17b-estradiol, down-regulates AT1R mRNA post-transcriptionally, and progesterone significantly increases AT1R mRNA by increased transcription and stabilizing mRNA. As early as 1997 (Samasura et al), some cytokines associated with atherosclerosis and inflammation were found to regulate AT1R expression. In more recent years, the picture has become clearer and AT1R is now believed to affect the development of atherosclerosis, myocardial infarction (heart attack), vascular and myocardial remodeling, and congestive heart failure (Nickenig et al 2002). The Importance of Investigating AT1R Transcriptional MechanismsDespite knowing some of the factors involved in, and consequences of, the expression of AGTR1, the molecular mechanism behind the regulation of the human gene is virtually unknown. Most studies investigating its transcriptional regulation have been done in rodents, but the rodent gene is not identical to the human gene (Nawata et al 1995). Because of the association of RAS genes with cardiovascular disease, it is important to understand the regulation of the human genes and determine the best treatments for patients suffering from genetic influences, but the work is slow. References:Mendelsohn, M. E. and Karas, R. H. Molecular and cellular basis of cardiovascular gender differences. Science 308: 1583-1587, 2005. Nickenig, G., Strehlow, K., Wassmann, S., Bäumer, A. T., Albory, K., Sauer, H., and Böhm, M. Differential effects of estrogen and progesterone on AT1 receptor gene expression in vascular smooth muscle cells. Circulation 102: 1828-1833, 2000.
The copyright of the article Human AGTR1 Expression in Human Genetics is owned by Alicia Mae Prater. Permission to republish Human AGTR1 Expression in print or online must be granted by the author in writing.
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