American journal of physiology. Heart and circulatory physiology, 2004-05, Vol.286 (5), p.H1954-H1962
2004
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- Autor(en) / Beteiligte
- Titel
- SAM68: a downstream target of angiotensin II signaling in vascular smooth muscle cells in genetic hypertension
- Ist Teil von
- American journal of physiology. Heart and circulatory physiology, 2004-05, Vol.286 (5), p.H1954-H1962
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2004
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada H2W 1R7 Submitted 26 January 2003 ; accepted in final form 19 December 2003 We investigated whether phosphatidylinositol 3-kinase (PI3K) and 68-kDa Src associated during mitosis (SAM68) are involved in angiotensin II (ANG II) growth signaling in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR). PI3K activity was assessed by measuring the phosphorylation of the regulatory subunit p85 and kinase activity of the catalytic 110-kDa subunit of PI3K. The PI3K-SAM68 interaction was assessed by coimmunoprecipitation, and SAM68 activity was evaluated by poly(U) binding. SAM68 expression was manipulated by SAM68 antisense oligonucleotide transfection. VSMC growth was evaluated by measuring [ 3 H]leucine and [ 3 H]thymidine incorporation as indexes of protein and DNA synthesis, respectively. ANG II increased the phosphorylation of p85 and kinase activity of the 110-kDa PI3K subunit in VSMCs from SHR and transiently increased p85 -SAM68 association. In Wistar-Kyoto (WKY) rat cells, ANG II increased SAM68 phosphorylation without influencing poly(U) binding. In SHR, ANG II did not influence SAM68 phosphorylation but increased SAM68 binding to poly(U). ANG II stimulated phosphoinositol phosphate synthesis by PI3K in SAM68 immunoprecipitates in both groups, with significantly enhanced effects in SHR. Inhibition of PI3K, using the selective inhibitor LY-294002, and downregulation of SAM68, by antisense oligonucleotides, significantly decreased ANG II-stimulated incorporation of [ 3 H]leucine and [ 3 H]thymidine in VSMCs, showing the functional significance of PI3K and SAM68. Our data demonstrate that PI3K and SAM68 are involved in ANG II signaling and that SAM68 is differentially regulated in VSMCs from SHR. These processes may contribute to the enhanced ANG II signaling and altered VSMC growth in SHR. growth; renin-angiotensin system; signal transduction; spontaneously hypertensive rat Address for reprint requests and other correspondence: E. L. Schiffrin, Clinical Research Institute of Montreal, 110 Pine Ave. West, Montreal, Quebec, Canada H2W 1R7 (E-mail: ernesto.schiffrin{at}ircm.qc.ca ).
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0363-6135eISSN: 1522-1539DOI: 10.1152/ajpheart.00134.2003Titel-ID: cdi_crossref_primary_10_1152_ajpheart_00134_2003
- Format
- –
- Schlagworte
- Angiotensin II - metabolism, Angiotensin II - pharmacology, Animals, Cell Division - drug effects, Cells, Cultured, Enzyme Inhibitors - pharmacology, Hypertension - genetics, Hypertension - metabolism, Muscle, Smooth, Vascular - metabolism, Muscle, Smooth, Vascular - pathology, Myocytes, Smooth Muscle - metabolism, Oligonucleotides, Antisense - pharmacology, Phosphatidylinositol 3-Kinases - antagonists & inhibitors, Phosphatidylinositol 3-Kinases - metabolism, Phosphorylation - drug effects, Poly U - metabolism, Protein Isoforms - metabolism, Rats, Rats, Inbred SHR, Rats, Inbred WKY, Receptor, Angiotensin, Type 1 - metabolism, RNA-Binding Proteins - genetics, RNA-Binding Proteins - metabolism, Signal Transduction - drug effects, Tissue Distribution