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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:441.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

CaMKII- Isoform Regulation of Neointima Formation After Vascular Injury

Suzanne J. House; Harold A. Singer

From the Center for Cardiovascular Sciences, Albany Medical College (MC-8), Albany, NY.

Correspondence to Harold A. Singer, PhD, Center for Cardiovascular Sciences (MC8), Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208-3479. E-mail singerh{at}mail.amc.edu

Abstract

Objective— The purpose of this study was to test the function of the calcium/calmodulin-dependent protein kinase II ₂ isoform (CaMKII₂) in regulating vascular smooth muscle (VSM) cell proliferation and migration in response to vascular injury.

Methods and Results— CaMKII isoform content was assessed in rat carotid arteries after balloon angioplasty–induced injury by Western blotting with isoform specific antibodies. Within 3 days after injury, a significant increase in CaMKII₂ and decrease in CaMKII isoform content was observed in both medial smooth muscle and adventitial fibroblasts. Neointimal VSM cells expressed primarily the ₂ isoform. Incubation of the injured vessel with adenovirus encoding siRNA targeting CaMKII isoforms prevented upregulation of the ₂ isoform in the media and adventitia; inhibited cell proliferation assessed by PCNA expression in both layers and markedly inhibited neointima formation and adventitial thickening.

Conclusions— CaMKII₂ is specifically induced in VSM and adventitial fibroblasts during the response of an artery to injury and is a positive regulator of proliferation and migration in the vessel wall contributing to neointima formation and vascular remodeling. This provides a potential mechanism for Ca²⁺-dependent regulation of VSM and myofibroblast proliferation and migration in response to vascular injury or disease.

We observed CaMKII isoform modulation in rat carotid artery in response to vascular injury. Attenuating CaMKII₂ upregulation using siRNA significantly decreased neointima formation and adventitial thickening. This finding is significant in that it provides a link whereby alterations in Ca²⁺ signaling directly contribute to vascular injury and disease.

Key Words: CaMKII • VSM proliferation • vascular injury • restenosis • neointima

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