Genetics

At1r and Cardiovascular Disease



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Cardiovascular disease includes coronary artery disease (including atherosclerosis and myocardial infarction), hypertension, and diabetes, to name a few. Research has found that some genes of the renin-angiotensin system (RAS) are associated with these diseases. The RAS increases blood pressure and affects the constriction of the blood vessels by activating the angiotensin II type 1 receptor (AT1R). The number of receptors available for activation is determined by the expression of the AT1R gene, and the number is thought to have some influence on the actions of the RAS. Complex genetic and hormonal mechanisms regulate both the expression and activity of the receptor.

Some cytokines associated with atherosclerosis and inflammation were found to regulate AT1R expression as early as 1997. 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.

The human AT1R gene is expressed in the adrenal glands, liver, kidneys, smooth muscle, brain, and fat tissue (called adipose). Transcriptional regulation of the gene is at the level of RNA production, which can be influenced by mutations in the DNA sequence that slow down or speed up the transcriptional machinery. Mutations have been recognized in the promoter region of the gene where the transcription machinery binds, which may influence transcription factor binding and the rate of transcription. If post-transcriptional processes are equal, individuals with particular mutations may have more AT1R being produced on a constant basis. In theory, increased receptors would lead to increased activation signals, leading to increases in blood pressure and potentially hypertension, as well as vasoconstriction and other cardiovascular events. In fact, angiotensin receptor blockers (ARBs) are used to treat some cardiovascular diseases, including hypertension.

Much more is known about the regulation of the AT1R protein. The 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 angiotensin II, the active molecule of the RAS. The receptor is down-regulated by the expression of angiotensin II, which is tied to the gene expression of its precursor molecule, angiotensinogen (AGT). This complicates the influence of gene expression on blood pressure and may even offer a balance if one gene is over-expressed.

Hormones play some role in the regulation of the receptor. Hyperinsulinemia (increased insulin levels, such as that seen in type 2 diabetes) has been associated with the physiological characteristics of hypertension, such as reduced sodium excretion from the kidneys, and insulin has been shown to affect AT1R gene expression in the smooth muscle cells of blood vessels by post-transcriptional mechanisms. In contrast, thyroid hormone has been found to down-regulate vascular AT1R at both the transcriptional and post-transcriptional levels, showing an ability to reverse the effects of the RAS.

Cardiovascular disease becomes more common in women as they age, especially after menopause. Estrogens also have a post-transcriptional affect on AT1R, down-regulating the receptor mRNA, and progesterone significantly increases AT1R mRNA by increasing transcription and stabilizing the mRNA.

Despite knowing some of the factors involved in, and consequences of, the expression of the AT1R gene, 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. 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.

Basic research studies of interest:

Dimitrijevic et al. Increased expression of endothelin ETB and angiotensin AT1 receptors in peripheral resistance arteries of patients with suspected acute coronary syndrome. Heart and Vessels 24: 393-398, 2009.

Elton and Martin. Alternative splicing: A novel mechanism to fine-tune the expression and function of the human AT1 receptor. Trends in Endocrinology and Metabolism 14: 66-71, 2003.

Fukuyama et al. Downregulation of vascular angiotensin II type 1 receptor by thyroid hormone. Hypertension 41: 598-603, 2003.

Kaschina and Unger. Angiotensin AT1/AT2 receptors: regulation, signalling, and function. Blood Pressure 12: 70-88, 2003.

Mendelsohn and Karas. Molecular and cellular basis of cardiovascular gender differences. Science 308: 1583-1587, 2005.

Nickenig et al. Insulin induces upregulation of vascular AT1 receptor gene expression by posttranscriptional mechanisms. Circulation 98: 2453-2460, 1998.

Nickenig et al. Differential effects of estrogen and progesterone on AT1 receptor gene expression in vascular smooth muscle cells. Circulation 102: 1828-1833, 2000.

Nickenig and Harrison. The AT(1)-type angiotensin receptor in oxidative stress and atherogenesis: part I: oxidative stress and atherogenesis. Circulation 105: 393-396, 2002.

Samasura et al. Regulation of vascular type 1 angiotensin receptors by cytokines. Hypertension 30: 35-41, 1997.

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