Oxidative activation of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates vascular smooth muscle migration and apoptosis

Abstract

Activation of the Ca2+/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 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.

S-Nitrosylation Induces Both Autonomous Activation and Inhibition of Calcium/Calmodulin-dependent Protein Kinase II δ

“…Oxidation-dependent activation of CaMKII␦ contributes to myocyte apoptosis during myocardial infarction (9), atrial fibrillation (30), and vascular smooth muscle cell migration after vascular injury (31). CaMKII␦ is also activated by O-GlcNAc modification, which contributes to hyperglycemia-induced Ca 2ϩ leaking and arrhythmia (10).…”

Protein methionine oxidation augments reperfusion injury in acute ischemic stroke

“…Mice expressing an oxidation-resistant CaMKII (M281/282V) were found to be protected from diabetes-attributable mortality after myocardial infarction (55). In the vasculature, CaMKII Met281/282 oxidation occurs in conditions of increased oxidative stress and promotes smooth muscle migration and apoptosis (60, 61). Importantly, CaMKII Met281/282 oxidation has been shown to be involved in regulation of the NF-κB pathway and inflammatory mechanisms associated with cardiac hypertrophy and asthma (26, 62).…”

Microvesicles Derived from Inflammation-Challenged Endothelial Cells Modulate Vascular Smooth Muscle Cell Functions

“…Vascular injury and inflammation affect the normal function of VSMC and play a major role in atherogenesis (Gambardella and Santulli, 2016). Various inflammatory cytokines, such as Tumor necrosis factor-α (TNF-α), Interferon-γ (IFN-γ), and Interleukin-2 (IL-2) have been associated with dysfunction in EC and VSMC, which are among the key contributors resulting in various vascular diseases, such as atherosclerosis (AS), hypertension, and vascular stenosis (Ho et al, 2010; Lu et al, 2013; Stone et al, 2013; Zhu et al, 2014). Studies have demonstrated that the pathogenesis of AS is closely associated with the dysregulation of VSMC proliferation, migration, and apoptosis (Shen et al, 2014; Zhu et al, 2014).…”

“…Various inflammatory cytokines, such as Tumor necrosis factor-α (TNF-α), Interferon-γ (IFN-γ), and Interleukin-2 (IL-2) have been associated with dysfunction in EC and VSMC, which are among the key contributors resulting in various vascular diseases, such as atherosclerosis (AS), hypertension, and vascular stenosis (Ho et al, 2010; Lu et al, 2013; Stone et al, 2013; Zhu et al, 2014). Studies have demonstrated that the pathogenesis of AS is closely associated with the dysregulation of VSMC proliferation, migration, and apoptosis (Shen et al, 2014; Zhu et al, 2014). EC provide an interface between blood and vessel walls, interact in close proximity with VSMC, and contribute to VSMC proliferation and migration (Nagel et al, 1994; Zitman-Gal et al, 2015).…”