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

Jason A Scott; Litao Xie; Hui Li; Weiwei Li; Julie B He; Philip N Sanders; A. Brent Carter; Johannes Backs; Mark E Anderson; Isabella M Grumbach

doi:10.1152/ajpheart.00978.2011

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

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

Jason A Scott, Litao Xie, Hui Li, Weiwei Li, Julie B He, Philip N Sanders, A. Brent Carter, Johannes Backs, Mark E Anderson and Isabella M Grumbach

American journal of physiology. Heart and circulatory physiology, Vol.302(10), pp.H1953-H1964

05/15/2012

DOI: 10.1152/ajpheart.00978.2011

PMCID: PMC3362103

PMID: 22427508

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Abstract

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 CaMKIIδ −/− 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 CaMKIIδ −/− mice. The perimeter of the external elastic lamina, a correlate of migration-related outward remodeling, was increased in WT but not in CaMKIIδ −/− mice. Migration induced by serum, platelet-derived growth factor, and tumor necrosis factor-α (TNF-α) was significantly decreased in CaMKIIδ −/− as compared with WT VSMCs, but migration was rescued with adenoviral overexpression of MMP9 in CaMKIIδ −/− VSMCs. Likewise, overexpression of CaMKIIδ in CaMKIIδ −/− VSMCs increased migration, whereas an oxidation-resistant mutant of CaMKIIδ did not. TNF-α strongly induced CaMKII oxidation and autophosphorylation as well as MMP9 activity, mRNA, and protein levels in WT, but not in CaMKIIδ −/− VSMC. Surprisingly, TNF-α strongly induced MMP9 promoter activity in WT and CaMKIIδ −/− VSMC. However, the MMP9 mRNA stability was significantly decreased in CaMKIIδ −/− VSMC. Our data demonstrate that CaMKII promotes VSMC migration through posttranscriptional regulation of MMP9 and suggest that CaMKII effects on MMP9 expression may be a therapeutic pathway in vascular injury.

Vascular Biology and Microcirculation

neointima

Details

Title: Subtitle: The multifunctional Ca2+/calmodulin-dependent kinase II regulates vascular smooth muscle migration through matrix metalloproteinase 9
Creators: Jason A Scott - Departments of
Litao Xie - Departments of
Hui Li - Departments of
Weiwei Li - Departments of
Julie B He - Departments of
Philip N Sanders - Departments of
A. Brent Carter - Departments of
Johannes Backs - Department of Internal Medicine III, University of Heidelberg, Germany
Mark E Anderson - Departments of
Isabella M Grumbach - Departments of
Resource Type: Journal article
Publication Details: American journal of physiology. Heart and circulatory physiology, Vol.302(10), pp.H1953-H1964
DOI: 10.1152/ajpheart.00978.2011
PMID: 22427508
PMCID: PMC3362103
NLM abbreviation: Am J Physiol Heart Circ Physiol
ISSN: 0363-6135
eISSN: 1522-1539
Publisher: American Physiological Society
Grant note: ES-015981; ES-014871 / National Institutes of Health
Language: English
Date published: 05/15/2012
Academic Unit: Pathology; Cardiovascular Medicine; Radiation Oncology; Internal Medicine
Record Identifier: 9984094211102771

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