Devil and angel in the renin-angiotensin system: ACE-angiotensin II-AT1 receptor axis vs. ACE2-angiotensin-(1-7)-Mas receptor axis.
Recent studies have established a new regulatory axis in the renin-angiotensin system (RAS). In this axis, angiotensin (Ang)-(1-7) is finally produced from Ang I or Ang II by the catalytic activity of angiotensin-converting enzyme 2 (ACE2). Ang-(1-7) shows actions different from those of AT(1) receptor stimulation, such as vasodilatation, natriuresis, anti-proliferation and an increase in the bradykinin-NO (nitric oxide) system. As the catalytic efficiency of ACE2 is approximately 400-fold higher with Ang II as a substrate than with Ang I, this axis is possibly acting as a counter-regulatory system against the ACE/Ang II/AT(1) receptor axis. The signaling pathway of the ACE2-Ang-(1-7) axis has not yet been totally and clearly understood. However, a recent report suggests that the Mas oncogene acts as a receptor for Ang-(1-7). Intracellular signaling through Mas is not clear yet. Several factors such as Akt phosphorylation, protein kinase C activation and mitogen-activated protein (MAP) kinase inhibition seem to be involved in this signaling pathway. Further investigations are needed to clarify the regulation and mechanism of action of ACE2 and Ang-(1-7). However, this second axis through ACE2 and Ang-(1-7) in RAS can be an important target for the therapy of cardiovascular and metabolic disorders.
Iwai
Masaru
M
Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon, Ehime, Japan.
Horiuchi
Masatsugu
M
D000803:Angiotensin I / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology*; D015398:Signal Transduction
D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)