title: Regulation of mitogen-activated protein kinase phosphatase-1 induction by insulin in vascular smooth muscle cells. Evaluation of the role of the nitric oxide signaling pathway and potential defects in hypertension.
abstract: In this study, we examined the regulation of mitogen-activated protein kinase phosphatase (MKP-1) expression by insulin in primary vascular smooth muscle cell cultures. Insulin caused a rapid time- and dose-dependent induction of MKP-1 mRNA and protein expression. Blockade of nitric-oxide synthase (NOS) with NG-monomethyl-L-arginine acetate, and cGMP with RpcGMP, completely inhibited MKP-1 expression. Insulin-mediated MKP-1 expression was preceded by inducible NOS (iNOS) induction and cGMP production. Blockade of phosphatidylinositol 3-kinase (PI3-kinase) signaling with wortmannin inhibited insulin-mediated iNOS protein induction, cGMP production, and MKP-1 expression. To evaluate potential interactions between NOS and the mitogen-activated protein kinase (MAPK) signaling pathways, we employed PD98059 and SB203580, two specific inhibitors of ERKs and p38 MAPK. These inhibitors abolished the effect of insulin on MKP-1 expression. Only PD98059 inhibited insulin-mediated iNOS protein induction. Vascular smooth muscle cells from spontaneous hypertensive rats exhibited a marked decrease in MKP-1 induction due to defects in insulin-induced iNOS expression because of reductions in PI3-kinase activity. Treatment with sodium nitroprusside and 8-bromo-cGMP restored MKP-1 mRNA expression to levels comparable with controls. We conclude that insulin-induced MKP-1 expression is mediated by PI3-kinase-initiated signals, leading to the induction of iNOS and elevated cGMP levels that stimulates MKP-1 expression.
authors.affiliation: Diabetes Research Laboratory, Winthrop University Hospital, Mineola, New York 11501, USA.
authors.forename: N
authors.initials: N
authors.lastname: Begum
authors.forename: L
authors.initials: L
authors.lastname: Ragolia
authors.forename: J
authors.initials: J
authors.lastname: Rienzie
authors.forename: M
authors.initials: M
authors.lastname: McCarthy
authors.forename: N
authors.initials: N
authors.lastname: Duddy
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D017874:Immediate-Early Proteins; D007328:Insulin; D011725:Pyridines; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases; D006152:Cyclic GMP; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin