Transgenic expression of an altered angiotensin type I AT1 receptor resulting in marked modulation of vascular type I collagen
| Autor: | Paul Toselli, Nicholas S. Hill, Jun Yu, Linda Taylor, Daniel S. Green, Philip J. Stone, Peter Polgar, Rod R. Warburton, Celeste B. Rich, Ronald H. Goldstein |
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| Rok vydání: | 2012 |
| Předmět: |
medicine.medical_specialty
Angiotensin receptor Receptor Bradykinin B2 Physiology Myocytes Smooth Muscle Clinical Biochemistry Mice Transgenic GTP-Binding Protein alpha Subunits Gi-Go Biology Bradykinin Article Collagen Type I Receptor Angiotensin Type 1 Mice Phosphatidylinositol 3-Kinases Internal medicine medicine Animals Transgenes Receptor Protein kinase B Aorta Cells Cultured PI3K/AKT/mTOR pathway Arachidonic Acid Angiotensin II receptor type 1 Angiotensin II Cell Biology Elastin Enzyme Activation Endocrinology cardiovascular system Signal transduction Protein Kinases Proto-Oncogene Proteins c-akt Type I collagen Signal Transduction |
| Zdroj: | Journal of Cellular Physiology. 227:2013-2021 |
| ISSN: | 0021-9541 |
| DOI: | 10.1002/jcp.22929 |
| Popis: | The angiotensin II 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 (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 angiotensin II 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 angiotensin II activated, while in the aSMCs from wild type mice the cascade was angiotensin II 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 angiotensin II. Akt and PI3K activation inhibitors blocked angiotensin II 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 angiotensin II with participation of Smad2 and Stat3 cascades in this process. |
| Databáze: | OpenAIRE |
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