SAM68: a downstream target of angiotensin II signaling in vascular smooth muscle cells in genetic hypertension

Mabrouk, M.E., Diep, Q.N., Benkirane, K., Touyz, R.M. and Schriffin, E.L. (2004) SAM68: a downstream target of angiotensin II signaling in vascular smooth muscle cells in genetic hypertension. American Journal of Physiology: Heart and Circulatory Physiology, 286(5), H1954-H1962. (doi: 10.1152/ajpheart.00134.2003)

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Publisher's URL: http://dx.doi.org/10.1152/ajpheart.00134.2003

Abstract

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 p85α 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 [3H]leucine and [3H]thymidine incorporation as indexes of protein and DNA synthesis, respectively. ANG II increased the phosphorylation of p85α and kinase activity of the 110-kDa PI3K subunit in VSMCs from SHR and transiently increased p85α-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 [3H]leucine and [3H]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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Touyz, Professor Rhian
Authors: Mabrouk, M.E., Diep, Q.N., Benkirane, K., Touyz, R.M., and Schriffin, E.L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:American Journal of Physiology: Heart and Circulatory Physiology
Journal Abbr.:AJP: Heart and circulatory physiology
ISSN:0363-6135
ISSN (Online):1522-1539
Published Online:23 December 2003

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