Mechanical stress modulates SOCS-1 expression in human vascular smooth muscle cells.
BACKGROUND
The growth-promoting effect of mechanical stress on vascular smooth muscle cells (VSMC) has been implicated in the progress of cardiovascular diseases related to elevated blood pressure. The underlying molecular mechanisms are, however, not completely defined.


METHODS
We have studied primary human aortic VSMC using a model for multilateral stretch. Expression of the suppressor of cytokine signaling (SOCS) family member SOCS-1 and related molecular mechanisms were studied using TaqMan analysis, immunoblotting, protein silencing, specific cell treatment, immunoprecipitation and immunocytochemistry.


RESULTS
Mechanical stretch inhibits SOCS-1 mRNA and protein expression. This effect was abolished by cell treatment with methyl-beta-cyclodextrin disrupting lipid rafts and with RGD peptide affecting integrins. Inhibition of integrin interaction with another cellular receptor, urokinase receptor (uPAR), as well as uPAR silencing also abolished stretch-induced SOCS-1 downregulation. Mechanical stretch resulted in uPAR redistribution to lipid rafts and in its colocalization with focal adhesion kinase (FAK). Stretch impairs polyubiquitination and proteosomal degradation of FAK leading to FAK upregulation in stretched VSMC. SOCS-1 silencing and inhibition of proteosomal degradation simulate this effect.


CONCLUSIONS
Our study identifies SOCS-1 as a novel participant involved in the propagation of mechanical stimuli in human VSMC, which might be relevant for the development of cardiovascular diseases.
Hannover Medical School, Hannover, Germany.
Marc
M
Dangers
Julia
J
Kiyan
Karsten
K
Grote
Bernhard
B
Schieffer
Hermann
H
Haller
Inna
I
Dumler
D002478:Cells, Cultured; D015536:Down-Regulation; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics; D013314:Stress, Mechanical; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis*; D015854:Up-Regulation
D055293:Receptors, Urokinase Plasminogen Activator; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human