title: Oxidative activation of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) regulates vascular smooth muscle migration and apoptosis.
abstract: Activation of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and reactive oxygen species (ROS) promote neointimal hyperplasia after vascular injury. CaMKII can be directly activated by ROS through oxidation. In this study, we determined whether abolishing the oxidative activation site of CaMKII alters vascular smooth muscle cell (VCMC) proliferation, migration and apoptosis in vitro and neointimal formation in vivo. VSMC isolated from a knock-in mouse with oxidation-resistant CaMKIIδ (CaMKII M2V) displayed similar proliferation but decreased migration and apoptosis. Surprisingly, ROS production and expression of the NADPH oxidase subunits p47 and p22 were decreased in M2V VSMC, whereas superoxide dismutase 2 protein expression was upregulated. In vivo, after carotid artery ligation, no differences in neointimal size or remodeling were observed. In contrast to VSMC, CaMKII expression and autonomous activity were significantly higher in M2V compared to WT carotid arteries, suggesting that an autoregulatory mechanism determines CaMKII activity in vivo. Our findings demonstrate that preventing oxidative activation of CaMKII decreases migration and apoptosis in vitro and suggest that CaMKII regulates ROS production. Our study presents novel evidence that CaMKII expression in vivo is regulated by a negative feedback loop following oxidative activation.
authors.affiliation: Department of Medicine, Iowa City, IA, United States.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Zhu
authors.affiliation: Department of Medicine, Iowa City, IA, United States.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Klutho
authors.affiliation: Department of Medicine, Iowa City, IA, United States.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Scott
authors.affiliation: Department of Medicine, Iowa City, IA, United States.
authors.forename: Litao
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Medicine, Iowa City, IA, United States.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Luczak
authors.affiliation: Department of Medicine, Iowa City, IA, United States.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Dibbern
authors.affiliation: Department of Medicine, Iowa City, IA, United States.
authors.forename: Anand M
authors.initials: AM
authors.lastname: Prasad
authors.affiliation: Department of Medicine, Iowa City, IA, United States.
authors.forename: Omar A
authors.initials: OA
authors.lastname: Jaffer
authors.affiliation: Department of Medicine, Iowa City, IA, United States.
authors.forename: Ashlee N
authors.initials: AN
authors.lastname: Venema
authors.affiliation: Department of Medicine, Iowa City, IA, United States.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Nguyen
authors.affiliation: Department of Medicine, Iowa City, IA, United States.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Guan
authors.affiliation: Department of Medicine, Iowa City, IA, United States; Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA, United States.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.affiliation: Department of Medicine, Iowa City, IA, United States; Iowa City VA Medical Center, Iowa City, IA, United States. Electronic address: isabella-grumbach@uiowa.edu.
authors.forename: Isabella M
authors.initials: IM
authors.lastname: Grumbach
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D002339:Carotid Arteries / Q000378:metabolism; D049109:Cell Proliferation; D003573:Cytochrome b Group / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D058426:Neointima / Q000378:metabolism; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003573:Cytochrome b Group; D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C515614:Cyba protein, mouse; C060505:neutrophil cytosolic factor 1
keywords: Apoptosis; CaMKII; Migration; Proliferation; Reactive oxygen species