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.
Skip Nav Destination
Article navigation
Research Article|
July 02 2014
Death-associated protein kinase 3 mediates vascular structural remodelling via stimulating smooth muscle cell proliferation and migration
Tatsuya Usui;
Tatsuya Usui
*Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan
Search for other works by this author on:
Tomoki Sakatsume;
Tomoki Sakatsume
*Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan
Search for other works by this author on:
Ryo Nijima;
Ryo Nijima
*Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan
Search for other works by this author on:
Kosuke Otani;
Kosuke Otani
*Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan
Search for other works by this author on:
Kyosuke Kazama;
Kyosuke Kazama
*Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan
Search for other works by this author on:
Tomoka Morita;
Tomoka Morita
*Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan
Search for other works by this author on:
Satoshi Kameshima;
Satoshi Kameshima
*Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan
Search for other works by this author on:
Muneyoshi Okada;
Muneyoshi Okada
*Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan
Search for other works by this author on:
Hideyuki Yamawaki
*Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Japan
Correspondence: Professor Hideyuki Yamawaki (email [email protected]).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
September 16 2013
Revision Received:
April 30 2014
Accepted:
May 12 2014
Accepted Manuscript online:
May 12 2014
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2014 Biochemical Society
2014
Clin Sci (Lond) (2014) 127 (8): 539–548.
Article history
Received:
September 16 2013
Revision Received:
April 30 2014
Accepted:
May 12 2014
Accepted Manuscript online:
May 12 2014
Citation
Tatsuya Usui, Tomoki Sakatsume, Ryo Nijima, Kosuke Otani, Kyosuke Kazama, Tomoka Morita, Satoshi Kameshima, Muneyoshi Okada, Hideyuki Yamawaki; Death-associated protein kinase 3 mediates vascular structural remodelling via stimulating smooth muscle cell proliferation and migration. Clin Sci (Lond) 1 October 2014; 127 (8): 539–548. doi: https://doi.org/10.1042/CS20130591
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Biochemical Society Member Sign in
Sign InSign in via your Institution
Sign in via your InstitutionGet Access To This Article
Open Access for all
We offer compliant routes for all authors from 2025. With library support, there will be no author nor reader charges in 5 journals. Check here |
![]() |