PMID- 20471392
OWN - NLM
STAT- MEDLINE
DCOM- 20101202
LR  - 20211020
IS  - 1095-8584 (Electronic)
IS  - 0022-2828 (Print)
IS  - 0022-2828 (Linking)
VI  - 49
IP  - 3
DP  - 2010 Sep
TI  - Uridine triphosphate (UTP) induces profibrotic responses in cardiac fibroblasts 
      by activation of P2Y2 receptors.
PG  - 362-9
LID - 10.1016/j.yjmcc.2010.05.001 [doi]
AB  - Cardiac fibroblasts (CFs) play a key role in response to injury and remodeling of 
      the heart. Nucleotide (P2) receptors regulate the heart but limited information 
      is available regarding such receptors in CFs. We thus sought to determine if 
      extracellular nucleotides regulate fibrotic responses (e.g., proliferation, 
      migration and expression of profibrotic markers) of CFs in primary culture. UTP 
      increased rat CF migration 3-fold (p<0.001), proliferation by 30% (p<0.05) and 
      mRNA expression of profibrotic markers: alpha smooth muscle actin (alpha-SMA), 
      plasminogen activator inhibitor-1 (PAI-1), transforming growth factor beta, 
      soluble ST2, interleukin-6 and monocyte chemoattractant protein-1 (MCP-1) by 
      3.0-, 15-, 2.0-, 7.6-, 11-, and 6.1-fold, respectively (p<0.05). PAI-1 protein 
      expression induced by UTP was dependent on protein kinase C (PKC) and 
      extracellular signal-regulated kinase (ERK), based on blockade by the PKC 
      inhibitor Ro-31-8220 and the ERK inhibitor U0126, respectively. The rank order 
      for enhanced expression of PAI-1 and alpha-SMA by nucleotides 
      (UTPgammaS>>UDPbetaS>>ATPgammaS), the expression of P2Y2 receptors as the most 
      abundantly expressed P2Y receptor in rat CFs and a blunted response to UTP in 
      P2Y2(-/-) mice all implicate P2Y2 as the predominant P2Y receptor that mediates 
      nucleotide-promoted profibrotic responses. Additional results indicate that P2Y2 
      receptor-promoted profibrotic responses in CFs are transient, perhaps as a 
      consequence of receptor desensitization. We conclude that P2Y2 receptor 
      activation is profibrotic in CFs; thus inhibition of P2Y2 receptors may provide a 
      novel means to diminish fibrotic remodeling and turnover of extracellular matrix 
      in the heart.
CI  - Copyright 2010 Elsevier Ltd. All rights reserved.
FAU - Braun, Oscar O
AU  - Braun OO
AD  - Department of Pharmacology, University of California San Diego, La Jolla, 
      California 92093, USA.
FAU - Lu, David
AU  - Lu D
FAU - Aroonsakool, Nakon
AU  - Aroonsakool N
FAU - Insel, Paul A
AU  - Insel PA
LA  - eng
GR  - P01 HL066941-090005/HL/NHLBI NIH HHS/United States
GR  - P01 HL066941/HL/NHLBI NIH HHS/United States
GR  - 2T32GM007752-32/GM/NIGMS NIH HHS/United States
GR  - 2P01HL066941/HL/NHLBI NIH HHS/United States
GR  - T32 GM007752/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100513
PL  - England
TA  - J Mol Cell Cardiol
JT  - Journal of molecular and cellular cardiology
JID - 0262322
RN  - 0 (Chemokine CCL2)
RN  - 0 (Interleukin-6)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Purinergic P2Y2)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - UT0S826Z60 (Uridine Triphosphate)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Chemokine CCL2/genetics/metabolism
MH  - Extracellular Signal-Regulated MAP Kinases/genetics/metabolism
MH  - Fibroblasts/*drug effects/metabolism
MH  - Flow Cytometry
MH  - Fluorescent Antibody Technique
MH  - Heart/*drug effects
MH  - Interleukin-6/genetics/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitogen-Activated Protein Kinases/genetics/metabolism
MH  - Plasminogen Activator Inhibitor 1/genetics/metabolism
MH  - Protein Kinase C/genetics/metabolism
MH  - RNA, Messenger/genetics
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Purinergic P2Y2/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Uridine Triphosphate/*pharmacology
PMC - PMC2917486
MID - NIHMS206420
EDAT- 2010/05/18 06:00
MHDA- 2010/12/14 06:00
PMCR- 2011/09/01
CRDT- 2010/05/18 06:00
PHST- 2009/08/26 00:00 [received]
PHST- 2010/04/29 00:00 [revised]
PHST- 2010/05/01 00:00 [accepted]
PHST- 2010/05/18 06:00 [entrez]
PHST- 2010/05/18 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
PHST- 2011/09/01 00:00 [pmc-release]
AID - S0022-2828(10)00183-5 [pii]
AID - 10.1016/j.yjmcc.2010.05.001 [doi]
PST - ppublish
SO  - J Mol Cell Cardiol. 2010 Sep;49(3):362-9. doi: 10.1016/j.yjmcc.2010.05.001. Epub 
      2010 May 13.