Oxysterol and diabetes activate STAT3 and control endothelial expression of profilin-1 via OSBP1.
Endothelial dysfunction plays a central role in diabetic vascular disease, but its molecular bases are not completely defined. We showed previously that the actin-binding protein proflin-1 was increased in the diabetic endothelium and that attenuated expression of profilin-1 protected against atherosclerosis. Also 7-ketocholesterol up-regulated profilin-1 in endothelial cells via transcriptional mechanisms. The present study addressed the pathways responsible for profilin-1 gene expression in 7-ketocholesterol-stimulated endothelial cells and in the diabetic aorta. In luciferase reporter assays, the response to 7-ketocholesterol within the 5'-flanking region of profilin-1 was dependent on a single STAT response element. In aortic endothelial cells, 7-ketocholesterol enhanced STAT3 activation, which required JAK2 and tyrosine 394 phosphorylation of oxysterol-binding protein-1. These changes were recapitulated in the aorta of diabetic rats. Also 7-ketocholesterol in cultured endothelial cells and diabetes in the aorta elicited the recruitment of STAT3 and relevant coregulatory factors to the oxysterol-responsive region of the profilin-1 promoter. These events were required for profilin-1 up-regulation. These studies identify a previously unrecognized oxysterol-binding protein-mediated mode of activation of STAT3 that controls the expression of the proatherogenic protein profilin-1 in response to 7-ketocholesterol and the diabetic milieu.
Romeo
Giulio R
GR
Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA. giulio.romeo@joslin.harvard.edu
Kazlauskas
Andrius
A
D000818:Animals; D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D007653:Ketocholesterols / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051304:Profilins / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D000098825:Oxysterol Binding Proteins
D007653:Ketocholesterols; D051304:Profilins; D011987:Receptors, Steroid; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D000098825:Oxysterol Binding Proteins; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; C003001:7-ketocholesterol