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Phosphatidylinositol 3-kinase/protein kinase Akt negatively regulates plasminogen activator inhibitor type 1 expression in vascular endothelial cells.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Mukai, Yasushi Wang, C. Rikitake, Yoshiyuki Liao, James K. |
| Copyright Year | 2007 |
| Abstract | Plasminogen activator inhibitor type 1 (PAI-1) regulates fibrinolytic activity and mediates vascular atherothrombotic disease. Endothelial cells (ECs) synthesize and secrete PAI-1, but the intracellular signaling pathways that regulate PAI-1 expression are not entirely known. We hypothesize that the phosphatidylinositol 3-kinase (PI3K)/protein kinase Akt pathway, which regulates endothelial function, could modulate PAI-1 expression in ECs. Cultured bovine aortic and human saphenous vein ECs were stimulated with TNF-alpha, ANG II, insulin, or serum, and PAI-1 expression was determined by Northern and Western analyses. Inhibition of PI3K with wortmannin or LY-294002 enhanced PAI-1 expression induced by these extracellular stimuli. Similarly, overexpression of a dominant-negative mutant of PI3K or Akt increased TNF-alpha- and insulin-induced PAI-1 expression. The increase in PAI-1 was due to transcriptional and posttranscriptional mechanisms as PI3K inhibitors increased PAI-1 promoter activity and mRNA stability. The induction of PAI-1 by TNF-alpha and insulin is mediated, in part, by ERK and p38 MAPK. PI3K inhibitors augmented TNF-alpha- and insulin-induced phosphorylation of these MAPKs. Simvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, which is known to activate PI3K/Akt, blocks TNF-alpha- and insulin-induced PAI-1 expression. Treatment with PI3K inhibitors reversed the inhibitor effects of simvastatin on TNF-alpha- and insulin-induced PAI-1 expression. These findings indicate that the PI3K/Akt pathway acts as a negative regulator of PAI-1 expression in ECs, in part, through the downregulation of MAPK pathways. These results suggest that factors that activate the PI3K/Akt pathway in ECs may have therapeutic benefits for atherothrombotic vascular disease. |
| Starting Page | 399 |
| Ending Page | 410 |
| Page Count | 12 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://ajpheart.physiology.org/content/ajpheart/292/4/h1937.full.pdf |
| Alternate Webpage(s) | http://ajpheart.physiology.org/content/ajpheart/292/4/H1937.full.pdf |
| PubMed reference number | 17172275v1 |
| Volume Number | 292 |
| Issue Number | 4 |
| Journal | American journal of physiology. Heart and circulatory physiology |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | 1-Phosphatidylinositol 3-Kinase Activation action Bos taurus Cell secretion Dominant-Negative Mutation Down-Regulation Endothelial Cells Endothelium LY 294002 Paget's Disease, Mammary Plasminogen Inactivators Protein Kinases Proto-Oncogene Proteins c-akt SERPINE1 protein, human Simvastatin Thrombolytic Therapy Transcription, Genetic Tumor Necrosis Factors Urokinase Vascular Diseases alteplase type I interferon receptor wortmannin |
| Content Type | Text |
| Resource Type | Article |
