title: Simvastatin potenciates PGI(2) release induced by HDL in human VSMC: effect on Cox-2 up-regulation and MAPK signalling pathways activated by HDL.
abstract: High density lipoproteins (HDL) induce prostacyclin (PGI(2)) release in vascular smooth muscle cells (VSMC) by up-regulation of cyclooxygenase-2 (Cox-2). Our goal was to analyse the mechanisms underlying this effect, and its potential modulation by HMG-CoA reductase inhibition in human VSMC. The contribution of mitogen-activated protein kinase (MAPK) signalling pathways was assessed by Western blot analysis and using specific inhibitors [PD098059 for p42/44 MAPK kinase (MEK); SB203580 for p38 MAPK or L-JNKI1 for c-Jun N-terminal kinase-1 (JNK-1)]. HDL-induced PGI(2) release was inhibited by rofecoxib (a specific Cox-2 inhibitor, 5 microM). HDL induced the early activation of p42 MAPK, p38 MAPK and JNK-1. p42/44 MAPK was the major pathway involved in both Cox-2 up-regulation and PGI(2) synthesis; p38 MAPK was also involved in both processes while JNK inhibition only affected PGI(2) synthesis. Pertussis toxin (an inhibitor of Galphai/Galphao proteins) prevented MAPK activation and inhibited both Cox-2 up-regulation and PGI(2) release. Genistein (a tyrosine kinase inhibitor) inhibited PGI(2) release without affecting MAPK activation or Cox-2 up-regulation. Simvastatin (0.1-1 microM) increased HDL-induced PGI(2) release ( approximately 45% at 1 microM) but did not significantly modify early MAPK activation or Cox-2 expression. Simvastatin alone did not significantly affect PGI(2) release. Our results suggest that mechanisms associated with G protein-coupled receptor activation, trigger Cox-2 up-regulation and PGI(2) release via multiple MAPK signalling pathways in VSMC. The mechanism is independent of tyrosine kinase receptors, although cytosolic tyrosine kinases could activate Cox-2 post-translationally. The potential contribution of HDL to vascular homeostasis, via increases in PGI(2) synthesis, could be enhanced by HMG-CoA reductase inhibitors.
authors.affiliation: Centro de Investigación Cardiovascular, CSIC/ICCC-Hospital de la Santa Creu i Sant Pau, Avda. Sant Antoni Maria Claret #167, 08025 Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Martínez-González
authors.forename: Itziar
authors.initials: I
authors.lastname: Escudero
authors.forename: Lina
authors.initials: L
authors.lastname: Badimon
mesh_terms: D000704:Analysis of Variance; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D011464:Epoprostenol / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007527:Isoenzymes; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D019821:Simvastatin; D011464:Epoprostenol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019950:Mitogen-Activated Protein Kinase 1