title: MEF2 is regulated by CaMKIIδ2 and a HDAC4-HDAC5 heterodimer in vascular smooth muscle cells.
abstract: 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 (Ca(2+)/calmodulin-dependent protein kinase) IIδ(2) 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 CaMKIIδ(2) 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 Ca(2+)- and CaMKIIδ(2)-dependent manner. We show further that AngII (angiotensin II)- and PDGF (platelet-derived growth factor)-dependent phosphorylation of HDAC4 and HDAC5 is reduced when CaMKIIδ(2) expression is suppressed or CaMKIIδ(2) 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 CaMKIIδ(2) 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 CaMKIIδ(2) mediates MEF2-dependent gene transcription in VSMCs through regulation of HDAC4 and HDAC5.
authors.affiliation: Center for Cardiovascular Sciences, Albany Medical College, NY 12208, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Ginnan
authors.forename: Li Yan
authors.initials: LY
authors.lastname: Sun
authors.forename: John J
authors.initials: JJ
authors.lastname: Schwarz
authors.forename: Harold A
authors.initials: HA
authors.lastname: Singer
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000502:physiology*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000502:physiology*; D007527:Isoenzymes / Q000502:physiology; D064326:MEF2 Transcription Factors; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D055503:Protein Multimerization; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D018932:Chemokine CCL2; D007527:Isoenzymes; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010982:Platelet-Derived Growth Factor; D000804:Angiotensin II; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; C559944:HDAC4 protein, rat; C498619:Hdac5 protein, rat; D006655:Histone Deacetylases