RGD Reference Report - Novel regulatory effect of angiotensin II type 1 receptor-interacting molecule on vascular smooth muscle cells. - Rat Genome Database

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Novel regulatory effect of angiotensin II type 1 receptor-interacting molecule on vascular smooth muscle cells.

Authors: Azuma, K  Tamura, K  Shigenaga, A  Wakui, H  Masuda, S  Tsurumi-Ikeya, Y  Tanaka, Y  Sakai, M  Matsuda, M  Hashimoto, T  Ishigami, T  Lopez-Ilasaca, M  Umemura, S 
Citation: Azuma K, etal., Hypertension. 2007 Nov;50(5):926-32. Epub 2007 Sep 17.
RGD ID: 2314353
Pubmed: PMID:17875818   (View Abstract at PubMed)
DOI: DOI:10.1161/HYPERTENSIONAHA.107.096115   (Journal Full-text)

We have recently cloned a novel molecule that interacts with the angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP). In this study, we tested the hypothesis that ATRAP modulates angiotensin II-induced responses in vascular smooth muscle cells. The results of immunoprecipitation and bioluminescence resonance energy transfer assay demonstrated a direct interaction between ATRAP and AT1R at baseline and showed that angiotensin II enhanced the interaction of these proteins >2-fold. The results of immunofluorescence analysis also demonstrated that >65% of ATRAP constitutively colocalized with an endosome marker. Although only 36% of ATRAP colocalized with AT1R at baseline, angiotensin II enhanced the colocalization of these molecules and made 92% of ATRAP colocalize with AT1R on a quantitative fluorescence analysis. Overexpression of ATRAP by adenoviral transfer decreased the cell surface AT1R number from 4.33 to 2.13 fmol/10(6) cells at baseline and from 3.04 to 1.26 fmol/10(6) cells even after removal of angiotensin II. ATRAP also suppressed angiotensin II-mediated increases in c-fos gene transcription and transforming growth factor-beta production. Furthermore, this suppression was accompanied by inhibition of angiotensin II-induced activation of 5-bromodeoxyuridine incorporation. Finally, ATRAP knockdown by small-interference RNA activated angiotensin II-induced c-fos gene expression, which was effectively inhibited by valsartan, an AT1R-specific antagonist. These results indicate that ATRAP promotes internalization of AT1R and attenuates the angiotensin II-mediated c-fos-transforming growth factor-beta pathway and proliferative response in vascular smooth muscle cells, suggesting a novel strategy to inhibit vascular fibrosis and remodeling through a novel and specific blockade of AT1R signaling.

Molecular Pathway Annotations    
Objects Annotated

Genes (Rattus norvegicus)
Agtrap  (angiotensin II receptor-associated protein)

Genes (Mus musculus)
Agtrap  (angiotensin II, type I receptor-associated protein)

Genes (Homo sapiens)
AGTRAP  (angiotensin II receptor associated protein)

Additional Information