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Title: ADP‐Induced Ca 2+ Signaling and Proliferation of Rat Ventricular Myofibroblasts Depend on Phospholipase C‐Linked TRP Channels Activation Within Lipid Rafts

Abstract

Nucleotides released during heart injury affect myocardium electrophysiology and remodeling through P2 purinoceptors activation in cardiac myofibroblasts. ATP and UTP endorse [Ca 2+ ] i accumulation and growth of DDR‐2/α‐SMA‐expressing myofibroblasts from adult rat ventricles via P2Y 4 and P2Y 2 receptors activation, respectively. Ventricular myofibroblasts also express ADP‐sensitive P2Y 1 , P2Y 12 , and P2Y 13 receptors as demonstrated by immunofluorescence confocal microscopy and western blot analysis, but little information exists on ADP effects in these cells. ADP (0.003–3 mM) and its stable analogue, ADPßS (100 μM), caused fast [Ca 2+ ] i transients originated from thapsigargin‐sensitive internal stores, which partially declined to a plateau sustained by capacitative Ca 2+ entry through transient receptor potential (TRP) channels inhibited by 2‐APB (50 μM) and flufenamic acid (100 μM). Hydrophobic interactions between G q/11 ‐coupled P2Y purinoceptors and TRP channels were suggested by prevention of the ADP‐induced [Ca 2+ ] i plateau following PIP 2 depletion with LiCl (10 mM) and cholesterol removal from lipid rafts with methyl‐ß‐cyclodextrin (2 mM). ADP [Ca 2+ ] i transients were insensitive to P2Y 1 , P2Y 12 , and P2Y 13 receptor antagonists, MRS2179 (10μM), AR‐C66096 (0.1 μM), and MRS2211 (10μM), respectively, but were attenuated by suramin and reactive blue‐2more » (100 μM) which also blocked P2Y 4 receptors activation by UTP. Cardiac myofibroblasts growth and type I collagen production were favored upon activation of MRS2179‐sensitive P2Y 1 receptors with ADP or ADPßS (30 μM). In conclusion, ADP exerts a dual role on ventricular myofibroblasts: [Ca 2+ ] i transients are mediated by fast‐desensitizing P2Y 4 receptors, whereas the pro‐fibrotic effect of ADP involves the P2Y 1 receptor activation. Data also show that ADP‐induced capacitative Ca 2+ influx depends on phospholipase C‐linked TRP channels opening in lipid raft microdomains. J. Cell. Physiol. 232: 1511–1526, 2017. © 2016 Wiley Periodicals, Inc.« less

Authors:
 [1];  [1];  [1];  [1];  [2];  [1]
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  1. Laboratório de Farmacologia e Neurobiologia, Centro de Investigação Farmacológica e Inovação Medicamentosa (MedInUP), Instituto de Ciências Biomédicas Abel Salazar Universidade do Porto (ICBAS‐UP) Porto Portugal
  2. Laboratório de Farmacologia e Neurobiologia, Centro de Investigação Farmacológica e Inovação Medicamentosa (MedInUP), Instituto de Ciências Biomédicas Abel Salazar Universidade do Porto (ICBAS‐UP) Porto Portugal, Departamento de Química, Instituto de Ciências Biomédicas Abel Salazar Universidade do Porto (ICBAS‐UP) Porto Portugal
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1401489
Resource Type:
Publisher's Accepted Manuscript
Journal Name:
Journal of Cellular Physiology
Additional Journal Information:
Journal Name: Journal of Cellular Physiology Journal Volume: 232 Journal Issue: 6; Journal ID: ISSN 0021-9541
Publisher:
Wiley Blackwell (John Wiley & Sons)
Country of Publication:
United States
Language:
English

Citation Formats

Certal, Mariana, Vinhas, Adriana, Barros‐Barbosa, Aurora, Ferreirinha, Fátima, Costa, Maria Adelina, and Correia‐de‐Sá, Paulo. ADP‐Induced Ca 2+ Signaling and Proliferation of Rat Ventricular Myofibroblasts Depend on Phospholipase C‐Linked TRP Channels Activation Within Lipid Rafts. United States: N. p., 2016. Web. doi:10.1002/jcp.25656.
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Certal, Mariana, Vinhas, Adriana, Barros‐Barbosa, Aurora, Ferreirinha, Fátima, Costa, Maria Adelina, & Correia‐de‐Sá, Paulo. ADP‐Induced Ca 2+ Signaling and Proliferation of Rat Ventricular Myofibroblasts Depend on Phospholipase C‐Linked TRP Channels Activation Within Lipid Rafts. United States. https://doi.org/10.1002/jcp.25656
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Certal, Mariana, Vinhas, Adriana, Barros‐Barbosa, Aurora, Ferreirinha, Fátima, Costa, Maria Adelina, and Correia‐de‐Sá, Paulo. Thu . "ADP‐Induced Ca 2+ Signaling and Proliferation of Rat Ventricular Myofibroblasts Depend on Phospholipase C‐Linked TRP Channels Activation Within Lipid Rafts". United States. https://doi.org/10.1002/jcp.25656.
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@article{osti_1401489,
title = {ADP‐Induced Ca 2+ Signaling and Proliferation of Rat Ventricular Myofibroblasts Depend on Phospholipase C‐Linked TRP Channels Activation Within Lipid Rafts},
author = {Certal, Mariana and Vinhas, Adriana and Barros‐Barbosa, Aurora and Ferreirinha, Fátima and Costa, Maria Adelina and Correia‐de‐Sá, Paulo},
abstractNote = {Nucleotides released during heart injury affect myocardium electrophysiology and remodeling through P2 purinoceptors activation in cardiac myofibroblasts. ATP and UTP endorse [Ca 2+ ] i accumulation and growth of DDR‐2/α‐SMA‐expressing myofibroblasts from adult rat ventricles via P2Y 4 and P2Y 2 receptors activation, respectively. Ventricular myofibroblasts also express ADP‐sensitive P2Y 1 , P2Y 12 , and P2Y 13 receptors as demonstrated by immunofluorescence confocal microscopy and western blot analysis, but little information exists on ADP effects in these cells. ADP (0.003–3 mM) and its stable analogue, ADPßS (100 μM), caused fast [Ca 2+ ] i transients originated from thapsigargin‐sensitive internal stores, which partially declined to a plateau sustained by capacitative Ca 2+ entry through transient receptor potential (TRP) channels inhibited by 2‐APB (50 μM) and flufenamic acid (100 μM). Hydrophobic interactions between G q/11 ‐coupled P2Y purinoceptors and TRP channels were suggested by prevention of the ADP‐induced [Ca 2+ ] i plateau following PIP 2 depletion with LiCl (10 mM) and cholesterol removal from lipid rafts with methyl‐ß‐cyclodextrin (2 mM). ADP [Ca 2+ ] i transients were insensitive to P2Y 1 , P2Y 12 , and P2Y 13 receptor antagonists, MRS2179 (10μM), AR‐C66096 (0.1 μM), and MRS2211 (10μM), respectively, but were attenuated by suramin and reactive blue‐2 (100 μM) which also blocked P2Y 4 receptors activation by UTP. Cardiac myofibroblasts growth and type I collagen production were favored upon activation of MRS2179‐sensitive P2Y 1 receptors with ADP or ADPßS (30 μM). In conclusion, ADP exerts a dual role on ventricular myofibroblasts: [Ca 2+ ] i transients are mediated by fast‐desensitizing P2Y 4 receptors, whereas the pro‐fibrotic effect of ADP involves the P2Y 1 receptor activation. Data also show that ADP‐induced capacitative Ca 2+ influx depends on phospholipase C‐linked TRP channels opening in lipid raft microdomains. J. Cell. Physiol. 232: 1511–1526, 2017. © 2016 Wiley Periodicals, Inc.},
doi = {10.1002/jcp.25656},
journal = {Journal of Cellular Physiology},
number = 6,
volume = 232,
place = {United States},
year = {Thu Nov 10 00:00:00 EST 2016},
month = {Thu Nov 10 00:00:00 EST 2016}
}
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https://doi.org/10.1002/jcp.25656
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Works referenced in this record:

Cyclodextrin-induced apoptosis in human keratinocytes is caspase-8 dependent and accompanied by mitochondrial cytochrome c release
journal, November 2006

Pyrimidine Nucleotides with 4-Alkyloxyimino and Terminal Tetraphosphate δ-Ester Modifications as Selective Agonists of the P2Y 4 Receptor
journal, June 2011

  • Maruoka, Hiroshi; Jayasekara, M. P. Suresh; Barrett, Matthew O.
  • Journal of Medicinal Chemistry, Vol. 54, Issue 12
  • DOI: 10.1021/jm101591j

Purinergic signaling in scarring
journal, January 2016

  • Ferrari, Davide; Gambari, Roberto; Idzko, Marco
  • The FASEB Journal, Vol. 30, Issue 1
  • DOI: 10.1096/fj.15-274563

Regulation of Canonical Transient Receptor Potential (TRPC) Channel Function by Diacylglycerol and Protein Kinase C
journal, April 2003

  • Venkatachalam, Kartik; Zheng, Fei; Gill, Donald L.
  • Journal of Biological Chemistry, Vol. 278, Issue 31
  • DOI: 10.1074/jbc.M302751200

Induction of Novel Agonist Selectivity for the ADP-Activated P2Y 1 Receptor Versus the ADP-Activated P2Y 12 and P2Y 13 Receptors by Conformational Constraint of an ADP Analog
journal, September 2004

  • Chhatriwala, Mariya; Ravi, R. Gnana; Patel, Roshni I.
  • Journal of Pharmacology and Experimental Therapeutics, Vol. 311, Issue 3
  • DOI: 10.1124/jpet.104.068650

Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2(+)-ATPase.
journal, April 1990

  • Thastrup, O.; Cullen, P. J.; Drobak, B. K.
  • Proceedings of the National Academy of Sciences, Vol. 87, Issue 7
  • DOI: 10.1073/pnas.87.7.2466

Calcium Signaling via Orai1 Is Essential for Induction of the Nuclear Orphan Receptor Pathway To Drive Th17 Differentiation
journal, December 2013

  • Kim, Kyun-Do; Srikanth, Sonal; Tan, Yossan-Var
  • The Journal of Immunology, Vol. 192, Issue 1
  • DOI: 10.4049/jimmunol.1302586

Store-operated CRAC channel inhibitors: opportunities and challenges
journal, May 2016

  • Tian, Chengsen; Du, Lupei; Zhou, Yubin
  • Future Medicinal Chemistry, Vol. 8, Issue 7
  • DOI: 10.4155/fmc-2016-0024

Pharmacological profiles of cloned mammalian P2Y-receptor subtypes
journal, June 2006

The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors: The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors
journal, December 2015

  • Alexander, Stephen PH; Davenport, Anthony P.; Kelly, Eamonn
  • British Journal of Pharmacology, Vol. 172, Issue 24
  • DOI: 10.1111/bph.13348

The effects of lithium on the phosphoinositides and inositol phosphates ofNeurospora crassa
journal, March 1991

Cardioprotective effects of KB-R7943: a novel inhibitor of the reverse mode of Na + /Ca 2+ exchanger
journal, June 1999

  • Ladilov, Y.; Haffner, S.; Balser-Schäfer, C.
  • American Journal of Physiology-Heart and Circulatory Physiology, Vol. 276, Issue 6
  • DOI: 10.1152/ajpheart.1999.276.6.H1868

The Na+/Ca2+ exchanger in cardiac ischemia/reperfusion injury
journal, January 2012

Ion Fluxes through KCa2 (SK) and Cav1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A1 Receptor-Mediated Actions in Spontaneously Beating Rat Atria
journal, March 2016

  • Bragança, Bruno; Oliveira-Monteiro, Nádia; Ferreirinha, Fátima
  • Frontiers in Pharmacology, Vol. 7
  • DOI: 10.3389/fphar.2016.00045

Structural and functional characterisation of cardiac fibroblasts
journal, January 2005

An Introduction to trp Channels
journal, January 2006

Fibroblasts in myocardial infarction: A role in inflammation and repair
journal, May 2014

Fibrosis and hypertensive heart disease
journal, January 2000

STIM1 elevation in the heart results in aberrant Ca2+ handling and cardiomyopathy
journal, October 2015

  • Correll, Robert N.; Goonasekera, Sanjeewa A.; van Berlo, Jop H.
  • Journal of Molecular and Cellular Cardiology, Vol. 87
  • DOI: 10.1016/j.yjmcc.2015.07.032

Molecular cloning and characterization of rat P2Y 4 nucleotide receptor
journal, June 1998

  • Bogdanov, Y. D.; Wildman, S. S.; Clements, M. P.
  • British Journal of Pharmacology, Vol. 124, Issue 3
  • DOI: 10.1038/sj.bjp.0701880

Transient Receptor Potential Canonical-3 Channel–Dependent Fibroblast Regulation in Atrial Fibrillation
journal, October 2012

Inositol phosphates and cell signalling
journal, September 1989

  • Berridge, Michael J.; Irvine, Robin F.
  • Nature, Vol. 341, Issue 6239
  • DOI: 10.1038/341197a0

The Living Scar – Cardiac Fibroblasts and the Injured Heart
journal, February 2016

Cardiac fibroblasts: At the heart of myocardial remodeling
journal, August 2009

The Caveolin genes: from cell biology to medicine
journal, January 2004

Flufenamic acid as an ion channel modulator
journal, May 2013

A Role for G-Proteins in Directing G-Protein-Coupled Receptor–Caveolae Localization
journal, November 2012

  • Calizo, Rhodora Cristina; Scarlata, Suzanne
  • Biochemistry, Vol. 51, Issue 47
  • DOI: 10.1021/bi301107p

Myofibroblasts: Trust your heart and let fate decide
journal, May 2014

A TRPC6-Dependent Pathway for Myofibroblast Transdifferentiation and Wound Healing In Vivo
journal, October 2012

Pharmacological Modulation of Diacylglycerol-Sensitive TRPC3/6/7 Channels
journal, January 2011

Potassium channel blockers differentially affect carbachol and (−)-N6-phenylisopropyladenosine on guinea-pig atria
journal, July 1989

Characterization of ion channels seen in subconfluent human dermal fibroblasts.
journal, May 1991

A simple method for preparation of cultured cardiac fibroblasts from adult human ventricular tissue
journal, January 1997

  • Agocha, Augustine E.; Eghbali-Webb, Mahboubeh
  • Molecular and Cellular Biochemistry, Vol. 172, Issue 1/2, p. 195-198
  • DOI: 10.1023/A:1006848512174

Critical Role for Stromal Interaction Molecule 1 in Cardiac Hypertrophy
journal, August 2011

THE CARDIAC FIBROBLAST: Therapeutic Target in Myocardial Remodeling and Failure
journal, September 2005

Purinergic signalling: Purinergic signalling
journal, January 2006

A distinct de novo expression of Na v 1.5 sodium channels in human atrial fibroblasts differentiated into myofibroblasts : Na
journal, August 2012

Nucleotide receptors as targets in the pharmacological enhancement of dermal wound healing
journal, April 2011

K + currents regulate the resting membrane potential, proliferation, and contractile responses in ventricular fibroblasts and myofibroblasts
journal, June 2005

  • Chilton, L.; Ohya, S.; Freed, D.
  • American Journal of Physiology-Heart and Circulatory Physiology, Vol. 288, Issue 6
  • DOI: 10.1152/ajpheart.01220.2004

P2Y 1 Receptor Activation of the TRPV4 Ion Channel Enhances Purinergic Signaling in Satellite Glial Cells
journal, October 2015

  • Rajasekhar, Pradeep; Poole, Daniel P.; Liedtke, Wolfgang
  • Journal of Biological Chemistry, Vol. 290, Issue 48
  • DOI: 10.1074/jbc.M115.689729

Cardiac Fibroblasts in Cell Culture Systems: Myofibroblasts All Along?
journal, January 2011

Caveolae Are Highly Immobile Plasma Membrane Microdomains, Which Are not Involved in Constitutive Endocytic Trafficking
journal, January 2002

  • Thomsen, Peter; Roepstorff, Kirstine; Stahlhut, Martin
  • Molecular Biology of the Cell, Vol. 13, Issue 1
  • DOI: 10.1091/mbc.01-06-0317

Nucleotide- and nucleoside-converting ectoenzymes: Important modulators of purinergic signalling cascade
journal, May 2008

Store-Operated Ca2+ Entry
book, January 2012

Impact of ectonucleotidases in autonomic nervous functions
journal, September 2015

  • Cardoso, Andréia Machado; Schetinger, Maria Rosa Chitolina; Correia-de-Sá, Paulo
  • Autonomic Neuroscience, Vol. 191
  • DOI: 10.1016/j.autneu.2015.04.014

The Collagen Receptor DDR2 Is Expressed During Early Cardiac Development
journal, May 2009

  • Goldsmith, Edie C.; Zhang, Xiadong; Watson, James
  • The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology, Vol. 293, Issue 5
  • DOI: 10.1002/ar.20922

Characterization of P2Y receptor subtypes functionally expressed on neonatal rat cardiac myofibroblasts
journal, September 2009

Orai1 and Stim1 regulate normal and hypertrophic growth in cardiomyocytes
journal, June 2010

  • Voelkers, Mirko; Salz, Mareen; Herzog, Nicole
  • Journal of Molecular and Cellular Cardiology, Vol. 48, Issue 6
  • DOI: 10.1016/j.yjmcc.2010.01.020

Adenosine-5′-triphosphate up-regulates proliferation of human cardiac fibroblasts: ATP and proliferation in human cardiac fibroblasts
journal, May 2012

Bradykinin-induced Ca2+ signaling in human subcutaneous fibroblasts involves ATP release via hemichannels leading to P2Y12 receptors activation
journal, January 2013

  • Pinheiro, Ana; Paramos-de-Carvalho, Diogo; Certal, Mariana
  • Cell Communication and Signaling, Vol. 11, Issue 1
  • DOI: 10.1186/1478-811X-11-70

Stimulation of P2Y receptors activates c-fos gene expression and inhibits DNA synthesis in cultured cardiac fibroblasts
journal, March 1998

Caveolin-1 alters Ca2+ signal duration through specific interaction with the G q family of G proteins
journal, April 2008

  • Sengupta, P.; Philip, F.; Scarlata, S.
  • Journal of Cell Science, Vol. 121, Issue 9
  • DOI: 10.1242/jcs.020081

TRPM7-Mediated Ca 2+ Signals Confer Fibrogenesis in Human Atrial Fibrillation
journal, March 2010

Uridine triphosphate (UTP) induces profibrotic responses in cardiac fibroblasts by activation of P2Y2 receptors
journal, September 2010

  • Braun, Oscar Ö.; Lu, David; Aroonsakool, Nakon
  • Journal of Molecular and Cellular Cardiology, Vol. 49, Issue 3
  • DOI: 10.1016/j.yjmcc.2010.05.001

A TRP to cardiac fibroblast differentiation
journal, May 2013

  • Thodeti, Charles K.; Paruchuri, Sailaja; Meszaros, J. Gary
  • Channels, Vol. 7, Issue 3
  • DOI: 10.4161/chan.24328

Caveolae: One Function or Many?
journal, March 2016

Metabotropic Purinergic Receptors in Lipid Membrane Microdomains
journal, December 2012

Calcineurin-dependent cardiomyopathy is activated by TRPC in the adult mouse heart
journal, August 2006

  • Nakayama, Hiroyuki; Wilkin, Benjamin J.; Bodi, Ilona
  • The FASEB Journal, Vol. 20, Issue 10
  • DOI: 10.1096/fj.05-5560com

TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals
journal, January 2013

  • Adapala, Ravi K.; Thoppil, Roslin J.; Luther, Daniel J.
  • Journal of Molecular and Cellular Cardiology, Vol. 54
  • DOI: 10.1016/j.yjmcc.2012.10.016

2-Aminoethoxydiphenyl borate (2-APB) is a reliable blocker of store-operated Ca 2+ entry but an inconsistent inhibitor of InsP 3 -induced Ca 2+ release
journal, August 2002

  • Bootman, Martin D.; Collins, Tony J.; Mackenzie, Lauren
  • The FASEB Journal, Vol. 16, Issue 10
  • DOI: 10.1096/fj.02-0037rev

Cellular Mechanisms of Tissue Fibrosis. 6. Purinergic signaling and response in fibroblasts and tissue fibrosis
journal, May 2014

Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling
journal, April 2016

Human mast cells stimulate fibroblast proliferation, collagen synthesis and lattice contraction: a direct role for mast cells in skin fibrosis
journal, February 2002

Role of ecto-NTPDases on UDP-sensitive P2Y 6 receptor activation during osteogenic differentiation of primary bone marrow stromal cells from postmenopausal women
journal, February 2012

  • Noronha-Matos, J. B.; Costa, M. A.; Magalhães-Cardoso, M. T.
  • Journal of Cellular Physiology, Vol. 227, Issue 6
  • DOI: 10.1002/jcp.23014

Cell Patterning: Interaction of Cardiac Myocytes and Fibroblasts in Three-Dimensional Culture
journal, March 2008

  • Baudino, Troy A.; McFadden, Alex; Fix, Charity
  • Microscopy and Microanalysis, Vol. 14, Issue 2
  • DOI: 10.1017/S1431927608080021

Origins of Cardiac Fibroblasts
journal, November 2010

Histamine Induces ATP Release from Human Subcutaneous Fibroblasts, via Pannexin-1 Hemichannels, Leading to Ca 2+ Mobilization and Cell Proliferation
journal, August 2013

  • Pinheiro, Ana Rita; Paramos-de-Carvalho, Diogo; Certal, Mariana
  • Journal of Biological Chemistry, Vol. 288, Issue 38
  • DOI: 10.1074/jbc.M113.460865

Calcium signaling and the novel anti-proliferative effect of the UTP-sensitive P2Y11 receptor in rat cardiac myofibroblasts
journal, November 2015

Guidelines for reporting experiments involving animals: the ARRIVE guidelines: Guidelines for reporting experiments involving animals
journal, July 2010

Caveolae and Caveolins in the Cardiovascular System
journal, June 2004

Expression of Discoidin Domain Receptor 2 (DDR2) in the Developing Heart
journal, May 2005

  • Morales, Mary O.; Price, Robert L.; Goldsmith, Edie C.
  • Microscopy and Microanalysis, Vol. 11, Issue 3
  • DOI: 10.1017/S1431927605050518
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