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Angiotensin II Receptors and Angiotensin II-Stimulated Signal Transduction

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Abstract

Originally known to be a vasoconstrictor and thought to play a critical role in hypertension, angiotensin II has recently emerged to be important in inflammation, atherosclerosis, and congestive heart failure. The discovery of selective angiotensin II receptor antagonists has enabled specific functions to be assigned to at least three angiotensin receptor subtypes (AT1, AT2, and AT4 receptors), which are expressed in a tissue-specific manner. Use of these antagonists resulted in the cloning and sequencing of two angiotensin II receptors (AT1 and AT2), which enabled a molecular analysis of angiotensin II binding sites to be performed. With these tools it has become possible to characterize the multiple signal transduction pathways activated by angiotensin II in a receptor- and tissue-specific manner. Initial studies have focused on the AT1 receptor inhibited by losartan and have defined structural domains responsible for G-protein coupling, activation of phospholipase C, and interactions with tyrosine kinases. Three major intracellular signal pathways associated with the AT1 receptor are activation of tyrosine kinases and downstream kinase cascades, stimulation of phospholipase C and increases in intracellular calcium, and inhibition of adenyl cyclase. Recent data show that angiotensin II not only stimulates cytoplasmic tyrosine kinases, including c-Src, focal adhesion kinase (FAK), and Janus kinases (JAK2 and TYK2), but also may transactivate receptor tyrosine kinases such as EGF Axl and PDGF by as yet undefined autocrine mechanisms. These angiotensin II-stimulated signal cascades appear to be required for angiotensin II effects such as vasoconstriction, proto-oncogene expression, protein synthesis, and cell proliferation. Advances in our knowledge of angiotensin II-mediated signaling events, especially those related to stimulation of kinase activity, may aid in development of new therapies for cardiovascular diseases.

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  1. Department of Medicine, Cardiology Unit, University of Rochester, Rochester, New York, USA

    Bradford C. Berk

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Berk, B.C. Angiotensin II Receptors and Angiotensin II-Stimulated Signal Transduction. Heart Fail Rev 3, 87–99 (1998). https://doi.org/10.1023/A:1009758627202

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