title: Transgenic expression of an altered angiotensin type I AT1 receptor resulting in marked modulation of vascular type I collagen.
abstract: The angiotensin II (AngII) type I receptor (AT1) was modified by replacing its third intracellular loop and C-terminal tail with the corresponding regions from the bradykinin B2 receptor. Transgenic mice were produced that overexpress this mutated receptor (AB3T). Considerably less collagen content in the intact aorta and in primary aortic smooth muscle cells (aSMCs) cultures was observed in the transgenic mice. On the other hand, elastin content remained unchanged as measured by Western blot, and insoluble amino acid quantitation. The contraction of isolated aortas also remained unaltered. The aSMCs derived from the transgenic mice showed a reduction in AngII responsive type I collagen production. In aSMCs from transgenic mice, the cascade of Akt to the mammalian target rapamycin (mTOR) to p70 S6 kinase (p70S6K) was not AngII activated, while in the aSMCs from wild-type (WT) mice the cascade was AngII activated. Angiotensin activation of Smad2 and Stat3 was also reduced in the AB3T aSMCs. However, no change in the effect of transforming growth factor β (TGFβ) on type I collagen production was observed. Also, the activation of ERK and JNK and G-protein linked signaling remained unaltered in response to AngII. Akt and PI3K activation inhibitors blocked AngII-stimulated type I collagen expression in WT aSMCs, whereas ERK inhibitor had no such effect. Our results point to an Akt/mTOR/p70S6K regulation of collagen production by AngII with participation of Smad2 and Stat3 cascades in this process.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Linda
authors.initials: L
authors.lastname: Taylor
authors.forename: Celeste
authors.initials: C
authors.lastname: Rich
authors.forename: Paul
authors.initials: P
authors.lastname: Toselli
authors.forename: Philip
authors.initials: P
authors.lastname: Stone
authors.forename: Daniel
authors.initials: D
authors.lastname: Green
authors.forename: Rod
authors.initials: R
authors.lastname: Warburton
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hill
authors.forename: Ronald
authors.initials: R
authors.lastname: Goldstein
authors.forename: Peter
authors.initials: P
authors.lastname: Polgar
mesh_terms: D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology; D016718:Arachidonic Acid / Q000378:metabolism; D001920:Bradykinin / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D004549:Elastin / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics* / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019076:Transgenes
chemical_list: D024042:Collagen Type I; D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; D000804:Angiotensin II; D016718:Arachidonic Acid; D004549:Elastin; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D001920:Bradykinin