CaMKII-δ isoform regulation of neointima formation after vascular injury

Objective - The purpose of this study was to test the function of the calcium/calmodulin-dependent protein kinase II delta(2) isoform (CaMKII delta(2)) 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 CaMKII delta(2) and decrease in CaMKII gamma isoform content was observed in both medial smooth muscle and adventitial fibroblasts. Neointimal VSM cells expressed primarily the delta(2) isoform. Incubation of the injured vessel with adenovirus encoding siRNA targeting CaMKII delta isoforms prevented upregulation of the delta(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 - CaMKII delta(2) 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.