Molecular and cellular mechanism of angiotensin II-mediated apoptosis.
It is well known that angiotensin II exerts growth promoting effects via the angiotensin II type 1 (AT1) receptor. We have cloned a second type of angiotensin II receptor (AT2 receptor) and demonstrated that this receptor acts as an antagonistic receptor against the AT1 receptor. Moreover, we have demonstrated that the AT2 receptor exerts growth inhibitory and proapoptotic effects by antagonizing the effects of the AT1 receptor and growth factors in several cell lines including vascular smooth muscle cells, cardiomyocytes, neuronal cell (PC12W) and fibroblasts (R3T3). We observed that the AT2 receptor activates tyrosine phosphatase(s) such as mitogen-activated protein (MAP) kinase-phosphatase-1 (MKP-1) and inactivates MAP kinase (extracellular signal-regulated kinase (ERK1 and ERK2)), resulting in Bcl-2 dephosphorylation and up-regulation of Bax. This inactivation of ERK is mediated via Gi protein coupling through its unique intracellular third loop. Moreover, we have demonstrated that interferon regulatory factor (IRF)-1 also up-regulates the AT2 receptor in apoptotic cells, suggesting that the cytokines may play an important role in angiotensin-regulated apoptosis.
Horiuchi
M
M
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Akishita
M
M
Dzau
V J
VJ
D016475:3T3 Cells; D000804:Angiotensin II / Q000235:genetics / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D003001:Cloning, Molecular; D004789:Enzyme Activation / Q000502:physiology; D006131:Growth Inhibitors / Q000502:physiology; D051379:Mice; D016716:PC12 Cells; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics / Q000502:physiology; D051028:bcl-2-Associated X Protein
D057911:Angiotensin Receptor Antagonists; C494827:Bax protein, mouse; C494828:Bax protein, rat; D006131:Growth Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D051028:bcl-2-Associated X Protein; D000804:Angiotensin II; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases