VSMCs (vascular smooth muscle cells) dedifferentiate from the contractile to the synthetic phenotype in response to acute vascular diseases such as restenosis and chronic vascular diseases such as atherosclerosis, and contribute to growth of the neointima. We demonstrated previously that balloon catheter injury of rat carotid arteries resulted in increased expression of CaMKII (Ca2+/calmodulin-dependent protein kinase) IIδ2 in the medial wall and the expanding neointima [House and Singer (2008) Arterioscler. Thromb. Vasc. Biol. 28, 441–447]. These findings led us to hypothesize that increased expression of CaMKIIδ2 is a positive mediator of synthetic VSMCs. HDAC (histone deacetylase) 4 and HDAC5 function as transcriptional co-repressors and are regulated in a CaMKII-dependent manner. In the present paper, we report that endogenous HDAC4 and HDAC5 in VSMCs are activated in a Ca2+- and CaMKIIδ2-dependent manner. We show further that AngII (angiotensin II)- and PDGF (platelet-derived growth factor)-dependent phosphorylation of HDAC4 and HDAC5 is reduced when CaMKIIδ2 expression is suppressed or CaMKIIδ2 activity is attenuated. The transcriptional activator MEF2 (myocyte-enhancer factor 2) is an important determinant of VSMC phenotype and is regulated in an HDAC-dependent manner. In the present paper, we report that stimulation of VSMCs with ionomycin or AngII potentiates MEF2's ability to bind DNA and increases the expression of established MEF2 target genes Nur77 (nuclear receptor 77) (NR4A1) and MCP1 (monocyte chemotactic protein 1) (CCL2). Suppression of CaMKIIδ2 attenuates increased MEF2 DNA-binding activity and up-regulation of Nur77 and MCP1. Finally, we show that HDAC5 is regulated by HDAC4 in VSMCs. Suppression of HDAC4 expression and activity prevents AngII- and PDGF-dependent phosphorylation of HDAC5. Taken together, these results illustrate a mechanism by which CaMKIIδ2 mediates MEF2-dependent gene transcription in VSMCs through regulation of HDAC4 and HDAC5.
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Research Article|
April 26 2012
MEF2 is regulated by CaMKIIδ2 and a HDAC4–HDAC5 heterodimer in vascular smooth muscle cells
Roman Ginnan;
Roman Ginnan
1Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208, U.S.A.
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Li Yan Sun;
Li Yan Sun
1Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208, U.S.A.
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John J. Schwarz;
John J. Schwarz
1Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208, U.S.A.
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Harold A. Singer
Harold A. Singer
1
1Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208, U.S.A.
1To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
January 23 2012
Accepted:
February 23 2012
Accepted Manuscript online:
February 23 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 444 (1): 105–114.
Article history
Received:
January 23 2012
Accepted:
February 23 2012
Accepted Manuscript online:
February 23 2012
Citation
Roman Ginnan, Li Yan Sun, John J. Schwarz, Harold A. Singer; MEF2 is regulated by CaMKIIδ2 and a HDAC4–HDAC5 heterodimer in vascular smooth muscle cells. Biochem J 15 May 2012; 444 (1): 105–114. doi: https://doi.org/10.1042/BJ20120152
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