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Transgenic expression of an altered angiotensin type I AT1 receptor resulting in marked modulation of vascular type I collagen
Author(s) -
Yu Jun,
Taylor Linda,
Rich Celeste,
Toselli Paul,
Stone Philip,
Green Daniel,
Warburton Rod,
Hill Nicholas,
Goldstein Ronald,
Polgar Peter
Publication year - 2012
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22929
Subject(s) - angiotensin ii receptor type 1 , angiotensin ii , receptor , transgene , microbiology and biotechnology , renin–angiotensin system , medicine , genetically modified mouse , modulation (music) , endocrinology , biology , chemistry , biochemistry , gene , physics , blood pressure , acoustics
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. J. Cell. Physiol. 227: 2013–2021, 2012. © 2011 Wiley Periodicals, Inc.