PMID- 25681429
OWN - NLM
STAT- MEDLINE
DCOM- 20151231
LR  - 20200930
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Linking)
VI  - 308
IP  - 8
DP  - 2015 Apr 15
TI  - Involvement of P2Y12 receptor in vascular smooth muscle inflammatory changes via 
      MCP-1 upregulation and monocyte adhesion.
PG  - H853-61
LID - 10.1152/ajpheart.00862.2013 [doi]
AB  - Antiplatelet drugs, frequently used for cardiovascular events with thrombotic 
      involvement, are also regarded as possible promising agents for cardiovascular 
      primary prevention. The roles of P2Y12, an ADP receptor and the target of 
      thienopyridine antiplatelet drugs, are not satisfactorily known in the vascular 
      wall. We investigated the hypothesis that vascular smooth muscle cell (VSMC) 
      P2Y12 is involved in vascular wall inflammatory changes by upregulating monocyte 
      chemoattractant protein-1 (MCP-1) and promoting monocyte adhesion. ADP at 10(-5) 
      M induced a 3.6 +/- 0.3-fold upregulation of MCP-1 mRNA in cultured rat VSMCs, 
      which was significantly inhibited by R-138727, the active metabolite of P2Y12 
      inhibitor prasugrel and siRNAs against P2Y12. ADP also induced MCP-1 protein 
      upregulation, which was diminished by R-138727 and P2Y12 siRNAs. JNK (c-Jun 
      NH2-terminal kinase) inhibition attenuated ADP-induced MCP-1 mRNA and protein 
      upregulation. R-138727 and P2Y12 siRNAs inhibited ADP-induced JNK activation. The 
      reactive oxygen species (ROS) inhibitors N-acetylcysteine (NAC), 
      diphenyleneiodonium (DPI), and Tempol also diminished MCP-1 upregulation and JNK 
      activation induced by ADP. ADP induced MCP-1 promoter activation, which was 
      inhibited by R-138727 and P2Y12 siRNAs. Nuclear factor-kappaB (NF-kappaB) consensus sites 
      in the MCP-1 promoter region were involved in this activation. ADP-induced NF-kappaB 
      pathway activation, examined by a plasmid containing multiple NF-kappaB sites, was 
      diminished by P2Y12 inhibition. For cellular function analysis, stimulation of 
      VSMC with ADP increased subsequent THP-1 monocyte adhesion. P2Y12 siRNAs and CCR2 
      antagonism diminished this ADP-induced monocyte adhesion. These data suggested 
      that ADP, via the VSMC P2Y12 receptor, induces vascular inflammatory changes by 
      upregulating MCP-1 and promoting monocyte adhesion.
CI  - Copyright (c) 2015 the American Physiological Society.
FAU - Satonaka, Hiroshi
AU  - Satonaka H
AD  - Department of Internal Medicine, Graduate School of Medicine, University of 
      Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan; hsatonak-tky@umin.ac.jp.
FAU - Nagata, Daisuke
AU  - Nagata D
AD  - Department of Internal Medicine, Graduate School of Medicine, University of 
      Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan;
FAU - Takahashi, Masao
AU  - Takahashi M
AD  - Department of Internal Medicine, Graduate School of Medicine, University of 
      Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan;
FAU - Kiyosue, Arihiro
AU  - Kiyosue A
AD  - Department of Internal Medicine, Graduate School of Medicine, University of 
      Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan;
FAU - Myojo, Masahiro
AU  - Myojo M
AD  - Department of Internal Medicine, Graduate School of Medicine, University of 
      Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan;
FAU - Fujita, Daishi
AU  - Fujita D
AD  - Department of Internal Medicine, Graduate School of Medicine, University of 
      Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan;
FAU - Ishimitsu, Toshihiko
AU  - Ishimitsu T
AD  - Department of Cardiology and Nephrology, Dokkyo Medical University, 
      Kitakobayashi, Mibu, Tochigi, Japan.
FAU - Nagano, Tetsuo
AU  - Nagano T
AD  - Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, 
      Bunkyo-ku, Tokyo; and.
FAU - Nagai, Ryozo
AU  - Nagai R
AD  - Department of Internal Medicine, Graduate School of Medicine, University of 
      Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan;
FAU - Hirata, Yasunobu
AU  - Hirata Y
AD  - Department of Internal Medicine, Graduate School of Medicine, University of 
      Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan;
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150213
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Ccl2 protein, rat)
RN  - 0 (Chemokine CCL2)
RN  - 0 (NF-kappa B)
RN  - 0 (Purinergic P2Y Receptor Antagonists)
RN  - 0 (RNA, Messenger)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, Purinergic P2Y12)
RN  - 61D2G4IYVH (Adenosine Diphosphate)
SB  - IM
MH  - Adenosine Diphosphate/pharmacology
MH  - Animals
MH  - Cell Adhesion
MH  - Cells, Cultured
MH  - Chemokine CCL2/genetics/*metabolism
MH  - Inflammation/metabolism
MH  - Male
MH  - Monocytes/drug effects/*metabolism/physiology
MH  - Muscle, Smooth, Vascular/*metabolism/pathology
MH  - NF-kappa B/metabolism
MH  - Purinergic P2Y Receptor Antagonists/pharmacology
MH  - RNA, Messenger/genetics/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Reactive Oxygen Species/metabolism
MH  - Receptors, Purinergic P2Y12/*metabolism
MH  - *Up-Regulation
OTO - NOTNLM
OT  - atherosclerosis
OT  - cytokines
OT  - inflammation
OT  - purinergic P2 receptors
OT  - vascular smooth muscle cell
EDAT- 2015/02/15 06:00
MHDA- 2016/01/01 06:00
CRDT- 2015/02/15 06:00
PHST- 2013/11/01 00:00 [received]
PHST- 2015/02/05 00:00 [accepted]
PHST- 2015/02/15 06:00 [entrez]
PHST- 2015/02/15 06:00 [pubmed]
PHST- 2016/01/01 06:00 [medline]
AID - ajpheart.00862.2013 [pii]
AID - 10.1152/ajpheart.00862.2013 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2015 Apr 15;308(8):H853-61. doi: 
      10.1152/ajpheart.00862.2013. Epub 2015 Feb 13.