MOLECULAR-BIOLOGY OF ANGIOTENSIN RECEPTORS AND THEIR ROLE IN HUMAN CARDIOVASCULAR-DISEASE

The actions of angiotensin II in the cardiovascular system are transmi tted by two known and possibly some unknown angiotensin receptor types . AT1 and AT2 both correspond to G-protein-coupled receptors with seve n hydrophobic transmembrane domains, several N-glycosylation sites and a potential G-protein binding site. Cloning of coding regions and pro moter sequences contributed to the understanding of receptor protein f unction and regulation. Angiotensin receptors with atypical binding pr operties for the known AT1- and AT2-specific ligands are expressed on human cardiac fibroblasts and in the human uterus. In several animal m odels, receptors with high affinity for angiotensin (1-7) have been de scribed. AT1 stimulation is mediated by the generation of phospholipid -derived second messengers, activation of protein kinase C, the MAPkin ase pathway and of immediate early genes. Recently, phosphorylation an d dephosphorylation of tyrosine kinases have been associated with AT1- and AT2-mediated signal transduction. ATR are regulated by phosphoryl ation, internalization, modification of transcription rate and mRNA st ability. Regulation is highly cell and organ specific and includes upr egulation of ATR in some pathophysiological situations where the renin angiotensin system is activated. Whereas the function of AT1 in the c ardiovascular system is relatively well established, there is little i nformation regarding the role of AT2. Recent hypotheses suggest an ant agonism between AT1 and AT2 at the signal transduction and the functio nal level. Transgenic animal models, particularly with targeted disrup tion of the AT1 and AT2 genes, suggest the contribution of both genes to blood pressure regulation. Genetic polymorphisms have been describe d in the AT1 and AT2 gene or neighbored regions and are used to analyz e the association between gene defects and cardiovascular diseases. AT 1 antagonists are now being introduced into the treatment of hypertens ion and potentially heart failure, and more interesting pharmacologica l developments are expected from the ongoing basic studies.