The multifunctional Ca2+/calmodulin-dependent kinase II regulates vascular smooth muscle migration through matrix metalloproteinase 9

Scott JA, Xie L, Li H, Li W, He JB, Sanders PN, Carter AB, Backs J, Anderson ME, Grumbach IM. The multifunctional Ca2+/calmodulin-dependent kinase II regulates vascular smooth muscle migration through matrix metalloproteinase 9. Am J Physiol Heart Circ Physiol 302: H1953-H1964, 2012. First published March 16, 2012; doi: 10.1152/ajpheart.00978.2011.-The multifunctional CaMKII has been implicated in vascular smooth muscle cell (VSMC) migration, but little is known regarding its downstream targets that mediate migration. Here, we examined whether CaMKII regulates migration through modulation of matrix metalloproteinase 9 (MMP9). Using CaMKII delta(-/-) mice as a model system, we evaluated migration and MMP9 regulation in vitro and in vivo. After ligation of the common carotid artery, CaMKII was activated in the neointima as determined by oxidation and autophosphorylation. We found that MMP9 was robustly expressed in the neointima and adventitia of carotid-ligated wild-type (WT) mice but was barely detectable in CaMKII delta(-/-) mice. The perimeter of the external elastic lamina, a correlate of migration-related outward remodeling, was increased in WT but not in CaMKII delta(-/-) mice. Migration induced by serum, platelet-derived growth factor, and tumor necrosis factor-alpha (TNF-alpha) was significantly decreased in CaMKII delta(-/-) as compared with WT VSMCs, but migration was rescued with adenoviral overexpression of MMP9 in CaMKII delta(-/-) VSMCs. Likewise, overexpression of CaMKII delta in CaMKII delta(-/-) VSMCs increased migration, whereas an oxidation-resistant mutant of CaMKII delta did not. TNF-alpha strongly induced CaMKII oxidation and autophosphorylation as well as MMP9 activity, mRNA, and protein levels in WT, but not in CaMKII delta(-/-) VSMC. Surprisingly, TNF-alpha strongly induced MMP9 promoter activity in WT and CaMKII delta(-/-) VSMC. However, the MMP9 mRNA stability was significantly decreased in CaMKII delta(-/-) VSMC. Our data demonstrate that CaMKII promotes VSMC migration through post-transcriptional regulation of MMP9 and suggest that CaMKII effects on MMP9 expression may be a therapeutic pathway in vascular injury.