Is the A(1166)C polymorphism of the angiotensin II type 1 receptor involved in cardiovascular disease?

Peptides produced by the renin-angiotensin system play a major role in the development and progression of various cardiovascular diseases. One of these peptides, angiotensin II, is a potent vasoconstrictor that exerts most of its effects through the human AT(1) receptor. Following the discovery of a functional variation in the angiotensin-converting enzyme gene, research has identified other genetic variations in the renin-angiotensin system that may contribute to cardiovascular disorders. Of the described polymorphisms in the AT(1)-receptor gene, the A(1166)C transversion is associated with human essential hypertension. We have used the TGR(alpha MHC-h AT(1)) rat model, which overexpresses the human AT(1) receptor in the myocardium. to study some of the associations between an increased AT(1) receptor number and cardiovascular disorders. Our results suggest that under physiological conditions overexpression of the AT(1) receptor causes no change in cardiovascular structure; however, pressure and volume overload lead to hypertrophic growth in this model. While the AT(1)-receptor polymorphism may not cause cardiovascular disorders directly, it can perhaps contribute to a process that is started by other factors, such as increased activity or uptake by tissues of plasma renin; which leads to local activation of the renin-angiotensin system. Our data indicate that the AT(1)-receptor polymorphism is probably associated with an increased responsiveness to angiotensin II. Under basal conditions, this increased responsiveness does not seem to affect the heart, but it may exert adverse effects under loading or high-renin conditions.