title: Death-associated protein kinase 3 mediates vascular structural remodelling via stimulating smooth muscle cell proliferation and migration.
abstract: Death-associated protein kinase 3 (DAPK3) also known as zipper-interacting kinase is a serine/threonine kinase that mainly regulates cell death and smooth muscle contraction. We have previously found that protein expression of DAPK3 increases in the mesenteric artery from spontaneously hypertensive rats (SHRs) and that DAPK3 mediates the development of hypertension in SHRs partly through promoting reactive oxygen species-dependent vascular inflammation. However, it remains to be clarified how DAPK3 controls smooth muscle cell (SMC) proliferation and migration, which are also important processes for hypertension development. We, therefore, sought to investigate whether DAPK3 affects SMC proliferation and migration. siRNA against DAPK3 significantly inhibited platelet-derived growth factor (PDGF)-BB-induced SMC proliferation and migration as determined by bromodeoxyuridine (BrdU) incorporation and a cell counting assay as well as a Boyden chamber assay respectively. DAPK3 siRNA or a pharmacological inhibitor of DAPK3 inhibited PDGF-BB-induced lamellipodia formation as determined by rhodamine-phalloidin staining. DAPK3 siRNA or the DAPK inhibitor significantly reduced PDGF-BB-induced activation of p38 and heat-shock protein 27 (HSP27) as determined by Western blotting. In ex vivo studies, PDGF-BB-induced SMC out-growth was significantly inhibited by the DAPK inhibitor. In vivo, the DAPK inhibitor significantly prevented carotid neointimal hyperplasia in a mouse ligation model. The present results, for the first time, revealed that DAPK3 mediates PDGF-BB-induced SMC proliferation and migration through activation of p38/HSP27 signals, which may lead to vascular structural remodelling including neointimal hyperplasia. The present study suggests DAPK3 as a novel pharmaceutical target for the prevention of hypertensive cardiovascular diseases.
authors.affiliation: *Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Usui
authors.affiliation: *Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Sakatsume
authors.affiliation: *Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nijima
authors.affiliation: *Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Otani
authors.affiliation: *Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Kazama
authors.affiliation: *Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan.
authors.forename: Tomoka
authors.initials: T
authors.lastname: Morita
authors.affiliation: *Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kameshima
authors.affiliation: *Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan.
authors.forename: Muneyoshi
authors.initials: M
authors.lastname: Okada
authors.affiliation: *Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamawaki
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D064550:Death-Associated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006965:Hyperplasia / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000201:enzymology; D058426:Neointima / Q000473:pathology; D010081:Oxazolone / Q000031:analogs & derivatives / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
chemical_list: D047428:Protein Kinase Inhibitors; D010081:Oxazolone; C579097:Dapk3 protein, rat; D064550:Death-Associated Protein Kinases