PMID- 17878405
OWN - NLM
STAT- MEDLINE
DCOM- 20071217
LR  - 20220318
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Linking)
VI  - 323
IP  - 3
DP  - 2007 Dec
TI  - Angiotensin-converting enzyme inhibitor attenuates monocyte adhesion to vascular 
      endothelium through modulation of intracellular zinc.
PG  - 855-60
AB  - To elucidate an anti-inflammatory role of angiotensin-converting enzyme 
      inhibitors (ACEIs) in cardiovascular disease, we studied the effect of ACEIs in 
      monocyte adhesion to endothelial cells and underlying molecular mechanisms. 
      Treatment of human monocytic THP-1 cells with monocyte chemoattractant protein-1 
      (MCP-1; 100 ng/ml; 10 min) significantly increased their adhesion to human 
      umbilical vein endothelial cells (HUVECs) under flow condition (P < 0.001). 
      Preincubation of THP-1 cells with imidaprilat (50 nM; 4 h), an active metabolite 
      of imidapril, reduced MCP-1-triggered THP-1 cell adhesion (P < 0.01). Similar 
      effects were obtained with experiments using human peripheral monocytes (P < 
      0.05). MCP-1 activated protein kinase C (PKC)alpha in THP-1 cells, resulting in 
      the up-regulation of alpha4 and beta2 integrin. Imidaprilat attenuated 
      MCP-1-induced PKC activation and integrin up-regulation in THP-1 cells. 
      Imidaprilat also inhibited THP-1 cell adhesion induced by phorbol 12-myristate 
      13-acetate (PMA), a potent PKC activator. In attempt to elucidate the mechanisms 
      for the modulation of PKC activity by imidaprilat, we found that MCP-1 or PMA 
      increased labile zinc in THP-1 cells, which was canceled by imidaprilat. Indeed, 
      zinc/pyrithione activated PKC and increased THP-1 cell adhesion. Zinc chelator as 
      well as PKC inhibitor inhibited these processes, suggesting the role for labile 
      zinc in PKC activation and THP-1 cell adhesion. Imidaprilat attenuated 
      zinc/pyrithione-induced PKC activation and THP-1 cell adhesion. These data 
      suggest that ACEI reduces MCP-1 or PMA-triggered monocyte adhesion to activated 
      HUVECs by modulating labile zinc in monocytes. Our findings may point out a novel 
      anti-inflammatory mechanism of ACEIs in atherogenesis.
FAU - Kojima, Chiari
AU  - Kojima C
AD  - Life Science and Bioethics Research Center, Tokyo Medical and Dental University, 
      1-5-45 Yushima Bldg. D-9, Bunkyo-ku, Tokyo 113-8519, Japan.
FAU - Kawakami, Akio
AU  - Kawakami A
FAU - Takei, Takashi
AU  - Takei T
FAU - Nitta, Kosaku
AU  - Nitta K
FAU - Yoshida, Masayuki
AU  - Yoshida M
LA  - eng
PT  - Journal Article
DEP - 20070918
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Angiotensin-Converting Enzyme Inhibitors)
RN  - 0 (Imidazolidines)
RN  - EC 3.4.15.1 (Peptidyl-Dipeptidase A)
RN  - WUU07Y30IA (imidaprilat)
SB  - IM
MH  - Angiotensin-Converting Enzyme Inhibitors/*pharmacology
MH  - Cell Adhesion/drug effects
MH  - Cell Line
MH  - Endothelial Cells/cytology/*drug effects
MH  - Endothelium, Vascular/cytology/*drug effects/metabolism
MH  - Flow Cytometry
MH  - Humans
MH  - Imidazolidines/*pharmacology
MH  - Immunoblotting
MH  - Monocytes/cytology/*drug effects
MH  - Peptidyl-Dipeptidase A/*metabolism
EDAT- 2007/09/20 09:00
MHDA- 2007/12/18 09:00
CRDT- 2007/09/20 09:00
PHST- 2007/09/20 09:00 [pubmed]
PHST- 2007/12/18 09:00 [medline]
PHST- 2007/09/20 09:00 [entrez]
AID - jpet.107.127944 [pii]
AID - 10.1124/jpet.107.127944 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2007 Dec;323(3):855-60. doi: 10.1124/jpet.107.127944. Epub 
      2007 Sep 18.