Disease relevance of Agtrap

• We found that an AT1-receptor (AT1-R) antagonist, TCV-116, inhibited tumor growth, tumor-associated angiogenesis, and metastasis in a murine model [1].
• CONCLUSION: Chronic AT1-receptor antagonism is capable of protecting the heart against myocardial infarction in a PKC-epsilon-dependent way [2].
• These studies have helped us identify genes that are essential to the development of AAAs (such as MMP9, IL6, and AT1R) and to reveal other genes that may be dispensable in aneurysm formation [3].
• cAbl tyrosine kinase mediates reactive oxygen species- and caveolin-dependent AT1 receptor signaling in vascular smooth muscle: role in vascular hypertrophy [4].
• These results indicate a fundamental role of AT1 receptor activation in atherogenesis [5].

Psychiatry related information on Agtrap

• Central angiotensin II controls alcohol consumption via its AT1 receptor [6].

High impact information on Agtrap

• We report here that intracellular factor XIIIA transglutaminase crosslinks agonist-induced AT1 receptor homodimers via glutamine315 in the carboxyl-terminal tail of the AT1 receptor [7].
• Factor XIIIA transglutaminase crosslinks AT1 receptor dimers of monocytes at the onset of atherosclerosis [7].
• Cardiac-specific overexpression of AT1 receptor mutant lacking G alpha q/G alpha i coupling causes hypertrophy and bradycardia in transgenic mice [8].
• Thus, the AT1 receptor mediates downstream signaling mechanisms through G(alpha)q/G(alpha)i-dependent and -independent mechanisms, which induce hypertrophy with a distinct phenotype [8].
• Thus, mechanical stress activates AT1 receptor independently of angiotensin II, and this activation can be inhibited by an inverse agonist of the AT1 receptor [9].

Chemical compound and disease context of Agtrap

• Activation of angiotensin II (Ang II) type 1 receptor (AT1R) signaling is reported to play an important role in cardiac hypertrophy [10].
• In addition, the effects of IL-6 on cardiomyocyte hypertrophy and fibroblast proliferation were inhibited by addition of the AT-1 receptor antagonist, losartan [11].
• Moreover, azelnidipine synergistically enhanced the inhibitory action of olmesartan on brain ischemia, suggesting beneficial combined effects of a CCB with an AT1 receptor blocker on ischemic brain damage [12].
• CONCLUSIONS: The AT1 receptor antagonist telmisartan ameliorated renal fibrosis after UUO by inhibition of oxidative stress, even under acatalasemic conditions [13].
• We p.o. administered the long-acting AT1R antagonist, candesartan (10 mg/kg), to the 16 days mouse renal cancer lung metastasis model to test the preventive effects in tumor metastasis [14].

Biological context of Agtrap

• We have recently cloned a new human gene cDNA that codes for a homolog of the murine Agtrap protein from a human fetal brain cDNA library [15].
• Stimulation of cultured rat aortic vascular smooth muscle cells (VSMCs) with IL-6 led to upregulation of AT1 receptor mRNA and protein expression, as assessed by Northern and Western blot experiments [16].
• Upregulation of vascular AT1 receptor expression in vitro and in vivo is decisively involved in IL-6-induced propagation of oxidative stress and endothelial dysfunction [16].
• Treatment of C57BL/6J mice with IL-6 for 18 days increased vascular AT1 receptor expression (real-time RT-PCR) and angiotensin II-induced vasoconstriction, enhanced vascular superoxide production (L-012 chemiluminescence, DHE fluorescence), and impaired endothelium-dependent vasodilatation [16].
• Nuclear run-on and transcription blockade experiments showed that IL-6 increases AT1 receptor mRNA de novo synthesis but not mRNA stability [16].

Anatomical context of Agtrap

• Caveolin therefore acts as a molecular chaperone rather than a plasma membrane scaffold for AT1-R [17].
• Despite the lack of AT1-R in caveolae, AT1-R.caveolin complexes are readily detectable in cells co-expressing both proteins [17].
• The mRNA of ATRAP was abundantly expressed in kidney, heart, and testis but was poorly expressed in lung, liver, spleen, and brain [18].
• In wild-type fibroblasts, Ang II increased collagen synthesis accompanied by an increase in expression of tissue inhibitor of metalloproteinase (TIMP)-1, and these increases were inhibited by valsartan, an AT1 receptor blocker, but augmented by PD123319, an AT2 receptor antagonist [19].
• Immunoreactive AT1-R was detected mainly on the neovascularized vascular endothelial cells in which expression was reduced by TCV-116 and lisinopril [1].

Associations of Agtrap with chemical compounds

• Cloning and characterization of ATRAP, a novel protein that interacts with the angiotensin II type 1 receptor [18].
• Mislocalization results in aberrant maturation and surface expression of AT1-R, effects that are not reversed by supplementing cells with cholesterol [17].
• CONCLUSION: The results indicate an Ang II-induced NO release in Af of mice, which is mediated by AT1-R [20].
• These findings show ATRAP to be abundantly and broadly distributed in nephron segments where the AT1 receptor is expressed [21].
• Stimulation of AT2-R during AT1-R inhibition with ZD7155, and preconstriction with norepinephrine (NE) had no influence on the diameter [20].

Physical interactions of Agtrap

• The selective AT2 receptor subtype antagonist PD 123319 (10 microM) was used to inhibit 125I-SI Ang II binding to AT2 receptors to determine AT1 receptor density in brain sections [22].

Regulatory relationships of Agtrap

• The carboxyl-terminal cytoplasmic domain of the angiotensin II type 1 (AT1) receptor has recently been shown to interact with several classes of cytoplasmic proteins that regulate different aspects of AT1 receptor physiology [18].
• Blockade of the AT1 receptor enhances the production of NO via the AT2 receptor in both wild-type and B2-null mice [23].
• CONCLUSIONS: AT1-R signaling blockade inhibited retinal ICAM-1 upregulation and leukocyte adhesion and infiltration in the EIU model [24].

Other interactions of Agtrap

• Effects of olmesartan, an AT1 receptor antagonist, on hypoxia-induced activation of ERK1/2 and pro-inflammatory signals in the mouse lung [25].
• Oral treatment of ApoE-/- mice with either hydralazine or irbesartan reduced systolic blood pressure to the same level; however, only AT1 receptor antagonist treatment reduced atherosclerotic lesion formation and improved endothelial function [5].
• The nonpeptide AT1 receptor blocker losartan antagonizes Ang II-induced [Ca2+]i increases in both cell groups, supporting mediation by native AT1B receptors and effective coupling of this subtype to second messenger systems leading to calcium entry and mobilization [26].
• CONCLUSION: These data indicate the existence of an opposite cross-talk of AT1R and AT2R with EGF receptors, and suggest a complex functional interaction between these pathways in the regulation of cellular growth processes [27].
• These data suggest that AT-1 receptor signaling pathways through EGFR may serve as a therapeutic target to inhibit the development of CKD [28].

Analytical, diagnostic and therapeutic context of Agtrap

• The ATRAP-AT1a receptor association was confirmed by affinity chromatography, by specific co-immunoprecipitation of the two proteins, and by fluorescence microscopy, showing co-localization of these proteins in intact cells [18].
• Electron microscopy of plasma membrane sheets shows that the AT1-R is not concentrated in caveolae but is clustered in cholesterol-independent microdomains; upon activation, it partially redistributes to lipid rafts [17].
• Employing in situ hybridization and immunohistochemistry, we found that both ATRAP mRNA and the protein were widely distributed along the renal tubules from Bowman's capsules to the inner medullary collecting ducts [21].
• The results of Western blot analysis revealed the ATRAP protein to be abundantly expressed in the kidney [21].
• RT-PCR showed expression of both AT1-R and AT2-R [20].

References