Oxidative activation of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) regulates vascular smooth muscle migration and apoptosis.

Zhu LJ, Klutho PJ, Scott JA, Xie L, Luczak ED, Dibbern ME, Prasad AM, Jaffer OA, Venema AN, Nguyen EK, Guan X, Anderson ME, Grumbach IM
Vascul Pharmacol. 2014 60 (2): 75-83

PMID: 24418021 · PMCID: PMC3955051 · DOI:10.1016/j.vph.2014.01.001

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 CaMKII╬┤ (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.

Published by Elsevier Inc.

MeSH Terms (17)

Animals Apoptosis Calcium-Calmodulin-Dependent Protein Kinase Type 2 Carotid Arteries Cell Proliferation Cytochrome b Group Female Gene Expression Regulation Gene Knock-In Techniques Male Mice Muscle, Smooth, Vascular NADPH Oxidases Neointima Oxidation-Reduction Reactive Oxygen Species Superoxide Dismutase

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