The Angiotensin II AT2 Receptor Is an AT1Receptor Antagonist

AbdAlla, Said; Lother, Heinz; Abdel‐tawab, Ahmed M.; Quitterer, Ursula

doi:10.1074/jbc.m105253200

Cited by 419 publications

(358 citation statements)

References 22 publications

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“…Further studies of investigating the difference of contractile function between maternal (adult) and fetal VSMCs would provide an answer. In addition, AbdAlla et al found AT2 receptor could bind directly to AT1 receptor in PC-12 cells and fetal fibroblasts thereby antagonize the function of the AT1 receptor [28]. Whether this accounts for the phenomenon observed in our study is not known.…”

Section: Discussionmentioning

confidence: 53%

Contractility of Placental Vascular Smooth Muscle Cells in Response to Stimuli Produced by the Placenta: Roles of ACE vs. Non-ACE and AT1 vs. AT2 in Placental Vessel Cells

Benoit

Zhang

et al. 2008

Placenta

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Our previously published work has shown that non-ACE angiotensin II (Ang II) generating system is dominate in the placenta and may play a critical role in regulation of placental vascular contractile function. In the present study, using a collagen gel contraction assay we further studied contractility of placental vascular smooth muscle cells (VSMCs) in response to factors produced by preeclamptic (PE) placentas. Placental VSMCs/type-1 collagen gels were incubated with PE placental conditioned medium in the presence or absence of inhibitors or receptor blockers. Captopril (an ACE inhibitor), chymostatin (a non-ACE chymase inhibitor), losartan (an AT1 receptor blocker) and PD123,319 (an AT2 receptor blocker) were used to study the specific ACE vs. non-ACE and AT1 vs. AT2 effects on placental VSMC contractility, respectively. Our results showed that chymostatin, but not captopril, and PD123,319, but not losartan, significantly attenuated placental VSMC/collagen gel contraction, p < 0.01, respectively. The inhibitory effects of chymostatin and PD123,319 were dosedependent. Our results suggest that chymase, a non-ACE Ang II generating enzyme, may contribute significantly to Ang II generated in the placenta vascular tissue and that the AT2 receptor may play an important role in the regulation of Ang II induced contractility of placental VSMCs. These results provide new insights into Ang II generation and Ang II receptor regulation of vessel contractile function in the placental vasculature. These results also suggest the potential role of increased chymase activity and altered AT2 receptor function in placental related pregnancy disorders such as preeclampsia and IUGR.

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Section: Discussionmentioning

confidence: 53%

Contractility of Placental Vascular Smooth Muscle Cells in Response to Stimuli Produced by the Placenta: Roles of ACE vs. Non-ACE and AT1 vs. AT2 in Placental Vessel Cells

Benoit

Zhang

et al. 2008

Placenta

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“…This may suggest a role for ATIP1 in AT2 receptor dimerization, a process of major importance for GPCR regulation and function (34,35). AT2 receptors have indeed been shown to heterodimerize with the AT1 subtype, and thereby inhibit the AT1 intracellular response by a novel mechanism that is independent of ligand/AT2 receptor interaction (36).…”

Section: Discussionmentioning

confidence: 96%

Trans-inactivation of Receptor Tyrosine Kinases by Novel Angiotensin II AT2 Receptor-interacting Protein, ATIP

Nouet

Amzallag

et al. 2004

Journal of Biological Chemistry

172

189

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Negative regulation of mitogenic pathways is a fundamental process that remains poorly characterized. The angiotensin II AT2 receptor is a rare example of a 7-transmembrane domain receptor that negatively cross-talks with receptor tyrosine kinases to inhibit cell growth. In the present study, we report the molecular cloning of a novel protein, ATIP1 (AT2-interacting protein), which interacts with the C-terminal tail of the AT2 receptor, but not with those of other receptors such as angiotensin AT1, bradykinin BK2, and adrenergic ␤ 2 receptor. ATIP1 defines a family of at least four members that possess the same domain of interaction with the AT2 receptor, contain a large coiled-coil region, and are able to dimerize. Ectopic expression of ATIP1 in eukaryotic cells leads to inhibition of insulin, basic fibroblast growth factor, and epidermal growth factor-induced ERK2 activation and DNA synthesis, and attenuates insulin receptor autophosphorylation, in the same way as the AT2 receptor. The inhibitory effect of ATIP1 requires expression, but not ligand activation, of the AT2 receptor and is further increased in the presence of Ang II, indicating that ATIP1 cooperates with AT2 to transinactivate receptor tyrosine kinases. Our findings therefore identify ATIP1 as a novel early component of growth inhibitory signaling cascade.The potent vasoactive peptide angiotensin II (Ang II) 1 is also an important regulator of cellular proliferation and hypertrophy. This peptide binds to two main subtypes of receptors (AT1 and AT2) that both belong to the superfamily of G proteincoupled receptors (GPCR) but display opposite biological and physiological effects. The AT1 receptor mediates most of the known cardiovascular and central actions of Ang II. This subtype has mitogenic and trophic effects in many tissues and cell types and transduces multiple intracellular signaling cascades typically associated with GPCR activation. In contrast, AT2 behaves like a "natural antagonist" of the AT1 subtype on most physiological functions, and induces anti-proliferative and proapoptotic effects in vitro and in vivo (for reviews, see Refs. 1-5).The AT2 receptor activates unconventional signaling pathways that in most cases do not involve coupling to classical regulatory G proteins. A growing body of evidence indicates that anti-growth effects of the AT2 receptor are associated with activation of tyrosine phosphatases and inhibition of protein kinases, which ultimately lead to inhibition of extracellular regulated kinase (ERK2). In many cell types, AT2 is functionally coupled to the Src homology 2 domain-containing tyrosine phosphatase SHP-1 (6 -8). This phosphatase has been shown to play a central role in the AT2 signaling cascades leading to inhibition of AT1-induced PYK2 and Jun kinase (9), AT1-transactivated EGF receptor tyrosine kinase (10), and insulin-induced phosphatidylinositol 3-kinase and Akt activation (11).AT2 negatively cross-talks with receptor tyrosine kinases (RTK) such as bFGF, EGF, and insulin receptors (10, 12, 13) by targeti...

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“…However, it has been shown that the different Ang II receptors can influence each other. [36][37][38][39][40] To exclude the possibility that the lack of one of the receptor subtypes alters the properties of the remaining receptors, we also investigated the effects of Ang-(1-7) in mice lacking all three Ang II receptor types. Although Ang-(1-7) was not able to reduce absolute MAP in the hypotensive triple KO mice, the percent changes induced by Ang-(1-7) were comparable with that in WT mice.…”

Section: Impact Ofmentioning

confidence: 99%

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

et al. 2012

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The renin-angiotensin system (RAS) has a vital role in regulating the cardiovascular system. The primary effector of the RAS is the octapeptide angiotensin (Ang) II, a potent regulator of blood pressure and water homeostasis. Ang II mediates its functions through the stimulation of two distinct receptors, AT 1 (two subtypes in rodents (AT 1a and AT 1b )) and AT 2 . It was shown that in addition to Ang II, shorter fragments of Ang are also biologically active. Ang-(1-7) came into focus because it opposes many of the detrimental effects of Ang II. However, it is still controversial whether Ang II receptors are involved in Ang-(1-7)-mediated signaling. To characterize the impacts of Ang II receptors on Ang-(1-7)-stimulated vascular relaxation, the effects of acute infusion of the three vasorelaxant compounds, that is, Ang-(1-7), bradykinin (BK) and acetylcholine (ACh), on heart rate (HR) and mean arterial pressure (MAP) were investigated in mice deficient for one, two or all three Ang II receptors. Ang-(1-7) and BK reduced MAP in wild-type, AT 1a /AT 1b -deficient and AT 2 -deficient mice. Although the change in absolute MAP values in the hypotensive triple knockouts (KO) could not be further reduced by both peptides, the percent change in MAP was comparable between the triple KO and wild-type mice. Both peptides did not alter the HR in all four genotypes. ACh significantly reduced absolute MAP values in all four genotypes with a similar percentage of reduction. In contrast to Ang-(1-7) and BK, ACh significantly reduced HR without genotypic differences. Our results generate proof that Ang-(1-7)-induced effects on MAP are mediated by a receptor that is independent of AT 1 and AT 2 .

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The Angiotensin II AT2 Receptor Is an AT1Receptor Antagonist

Cited by 419 publications

References 22 publications

Contractility of Placental Vascular Smooth Muscle Cells in Response to Stimuli Produced by the Placenta: Roles of ACE vs. Non-ACE and AT1 vs. AT2 in Placental Vessel Cells

Contractility of Placental Vascular Smooth Muscle Cells in Response to Stimuli Produced by the Placenta: Roles of ACE vs. Non-ACE and AT1 vs. AT2 in Placental Vessel Cells

Trans-inactivation of Receptor Tyrosine Kinases by Novel Angiotensin II AT2 Receptor-interacting Protein, ATIP

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

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