PMID- 20089806
OWN - NLM
STAT- MEDLINE
DCOM- 20100422
LR  - 20211203
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 333
IP  - 1
DP  - 2010 Apr
TI  - Cyclosporine up-regulates Kruppel-like factor-4 (KLF4) in vascular smooth muscle 
      cells and drives phenotypic modulation in vivo.
PG  - 34-42
LID - 10.1124/jpet.109.163949 [doi]
AB  - Cyclosporine A (CSA, calcineurin inhibitor) has been shown to block both vascular 
      smooth muscle cell (VSMC) proliferation in cell culture and vessel neointimal 
      formation following injury in vivo. The purpose of this study was to determine 
      molecular and pathological effects of CSA on VSMCs. Using real-time reverse 
      transcription-polymerase chain reaction, Western blot analysis, and 
      immunofluorescence microscopy, we show that CSA up-regulated the expression of 
      Kruppel-like factor-4 (KLF4) in VSMCs. KLF4 plays a key role in regulating VSMC 
      phenotypic modulation. KLF4 antagonizes proliferation, facilitates migration, and 
      down-regulates VSMC differentiation marker gene expression. We show that the VSMC 
      differentiation marker genes smooth muscle alpha-actin (ACTA2), transgelin 
      (TAGLN), smoothelin (SMTN), and myocardin (MYOCD) are all down-regulated by CSA 
      in VSMC monoculture, whereas cyclin-dependent kinase inhibitor-1A (CDKN1A) and 
      matrix metalloproteinase-3 (MMP3) are up-regulated. CSA did not affect the 
      abundance of the VSMC microRNA (MIR) markers MIR143 and MIR145. Administration of 
      CSA to rat carotid artery in vivo resulted in acute and transient suppression of 
      ACTA2, TAGLN, SMTN, MYOCD, and smooth muscle myosin heavy chain (MYH11) mRNA 
      levels. The tumor suppressor genes KLF4, p53, and CDKN1A, however, were 
      up-regulated, as well as MMP3, MMP9, and collagen-VIII. CSA-treated arteries 
      showed remarkable remodeling, including breakdown of the internal elastic lamina 
      and reorientation of VSMCs, as well as increased KLF4 immunostaining in VSMCs and 
      endothelial cells. Altogether, these data show that cyclosporin up-regulates KLF4 
      expression and promotes phenotypic modulation of VSMCs.
FAU - Garvey, Sean M
AU  - Garvey SM
AD  - Department of Medicine, Division of Cardiovascular Medicine, University of 
      Virginia, Charlottesville, VA, USA.
FAU - Sinden, Daniel S
AU  - Sinden DS
FAU - Schoppee Bortz, Pamela D
AU  - Schoppee Bortz PD
FAU - Wamhoff, Brian R
AU  - Wamhoff BR
LA  - eng
GR  - R01 HL081682/HL/NHLBI NIH HHS/United States
GR  - T32 GM007171/GM/NIGMS NIH HHS/United States
GR  - R01-HL081682/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100120
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Antigens, Differentiation)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Klf4 protein, rat)
RN  - 0 (Kruppel-Like Factor 4)
RN  - 0 (Kruppel-Like Transcription Factors)
RN  - 83HN0GTJ6D (Cyclosporine)
SB  - IM
MH  - Animals
MH  - Antigens, Differentiation/metabolism
MH  - Aorta/cytology
MH  - Carotid Arteries/drug effects/pathology
MH  - Cell Differentiation
MH  - Cells, Cultured
MH  - Cyclosporine/adverse effects/*pharmacology
MH  - Down-Regulation
MH  - Immunosuppressive Agents/adverse effects/*pharmacology
MH  - Kruppel-Like Factor 4
MH  - Kruppel-Like Transcription Factors/*biosynthesis
MH  - Myocytes, Smooth Muscle/cytology/*drug effects/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Tunica Media/drug effects/pathology
MH  - Up-Regulation
PMC - PMC2846029
EDAT- 2010/01/22 06:00
MHDA- 2010/04/23 06:00
PMCR- 2011/04/01
CRDT- 2010/01/22 06:00
PHST- 2010/01/22 06:00 [entrez]
PHST- 2010/01/22 06:00 [pubmed]
PHST- 2010/04/23 06:00 [medline]
PHST- 2011/04/01 00:00 [pmc-release]
AID - jpet.109.163949 [pii]
AID - 3572689 [pii]
AID - 10.1124/jpet.109.163949 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2010 Apr;333(1):34-42. doi: 10.1124/jpet.109.163949. Epub 
      2010 Jan 20.