PMID- 22360269
OWN - NLM
STAT- MEDLINE
DCOM- 20120709
LR  - 20211021
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Print)
IS  - 0264-6021 (Linking)
VI  - 444
IP  - 1
DP  - 2012 May 15
TI  - MEF2 is regulated by CaMKIIdelta2 and a HDAC4-HDAC5 heterodimer in vascular smooth 
      muscle cells.
PG  - 105-14
LID - 10.1042/BJ20120152 [doi]
AB  - 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) IIdelta(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 
      CaMKIIdelta(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 CaMKIIdelta(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 CaMKIIdelta(2) 
      expression is suppressed or CaMKIIdelta(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 CaMKIIdelta(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 CaMKIIdelta(2) 
      mediates MEF2-dependent gene transcription in VSMCs through regulation of HDAC4 
      and HDAC5.
FAU - Ginnan, Roman
AU  - Ginnan R
AD  - Center for Cardiovascular Sciences, Albany Medical College, NY 12208, USA.
FAU - Sun, Li Yan
AU  - Sun LY
FAU - Schwarz, John J
AU  - Schwarz JJ
FAU - Singer, Harold A
AU  - Singer HA
LA  - eng
GR  - R01 HL049426/HL/NHLBI NIH HHS/United States
GR  - R01 HL092510/HL/NHLBI NIH HHS/United States
GR  - R01-HL-092510/HL/NHLBI NIH HHS/United States
GR  - R01-HL-49426/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Chemokine CCL2)
RN  - 0 (Isoenzymes)
RN  - 0 (MEF2 Transcription Factors)
RN  - 0 (Myogenic Regulatory Factors)
RN  - 0 (Nr4a1 protein, rat)
RN  - 0 (Nuclear Receptor Subfamily 4, Group A, Member 1)
RN  - 0 (Platelet-Derived Growth Factor)
RN  - 11128-99-7 (Angiotensin II)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 1)
RN  - EC 3.5.1.98 (HDAC4 protein, rat)
RN  - EC 3.5.1.98 (Hdac5 protein, rat)
RN  - EC 3.5.1.98 (Histone Deacetylases)
SB  - IM
MH  - Angiotensin II/pharmacology
MH  - Animals
MH  - Aorta, Thoracic/cytology
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 1/*physiology
MH  - Chemokine CCL2/genetics/metabolism
MH  - Histone Deacetylases/*physiology
MH  - Isoenzymes/physiology
MH  - MEF2 Transcription Factors
MH  - Muscle, Smooth, Vascular/cytology/*metabolism
MH  - Myocytes, Smooth Muscle/*metabolism
MH  - Myogenic Regulatory Factors/*metabolism
MH  - Nuclear Receptor Subfamily 4, Group A, Member 1/genetics/metabolism
MH  - Platelet-Derived Growth Factor/pharmacology
MH  - Protein Multimerization
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction
MH  - Transcription, Genetic
PMC - PMC3632366
MID - NIHMS452960
EDAT- 2012/03/01 06:00
MHDA- 2012/07/10 06:00
PMCR- 2013/04/22
CRDT- 2012/02/25 06:00
PHST- 2012/02/25 06:00 [entrez]
PHST- 2012/03/01 06:00 [pubmed]
PHST- 2012/07/10 06:00 [medline]
PHST- 2013/04/22 00:00 [pmc-release]
AID - BJ20120152 [pii]
AID - 10.1042/BJ20120152 [doi]
PST - ppublish
SO  - Biochem J. 2012 May 15;444(1):105-14. doi: 10.1042/BJ20120152.