Is the A1166C 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 AT1 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 AT1-receptor gene, the A1166C transversion is associated with human essential hypertension. We have used the TGR(alpha MHC-h AT1) rat model, which overexpresses the human AT1 receptor in the myocardium, to study some of the associations between an increased AT1-receptor number and cardiovascular disorders. Our results suggest that under physiological conditions overexpression of the AT1 receptor causes no changes in cardiovascular structure; however, pressure and volume overload lead to hypertrophic growth in this model. While the AT1-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 AT1-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.
Department of Clinical Pharmacology, University of Groningen, The Netherlands.
P P
PP
van Geel
Y M
YM
Pinto
H
H
Buikema
W H
WH
van Gilst
D000818:Animals; D002318:Cardiovascular Diseases / Q000235:genetics*; D015870:Gene Expression / Q000502:physiology; D014644:Genetic Variation; D006801:Humans; D006973:Hypertension / Q000235:genetics; D009206:Myocardium / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics*
D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D007703:Peptidyl-Dipeptidase A