title: Antithrombotic actions of statins involve PECAM-1 signaling.
abstract: Statins are widely prescribed cholesterol-lowering drugs that are a first-line treatment of coronary artery disease and atherosclerosis, reducing the incidence of thrombotic events such as myocardial infarction and stroke. Statins have been shown to reduce platelet activation, although the mechanism(s) through which this occurs is unclear. Because several of the characteristic effects of statins on platelets are shared with those elicited by the inhibitory platelet adhesion receptor PECAM-1 (platelet endothelial cell adhesion molecule-1), we investigated a potential connection between the influence of statins on platelet function and PECAM-1 signaling. Statins were found to inhibit a range of platelet functional responses and thrombus formation in vitro and in vivo. Notably, these effects of statins on platelet function in vitro and in vivo were diminished in PECAM-1(-/-) platelets. Activation of PECAM-1 signaling results in its tyrosine phosphorylation, the recruitment and activation of tyrosine phosphatase SHP-2, the subsequent binding of phosphoinositol 3-kinase (PI3K), and diminished PI3K signaling. Statins resulted in the stimulation of these events, leading to the inhibition of Akt activation. Together, these data provide evidence for a fundamental role of PECAM-1 in the inhibitory effects of statins on platelet activation, which may explain some of the pleiotropic actions of these drugs.
authors.affiliation: Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom.
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Moraes
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Vaiyapuri
authors.forename: Parvathy
authors.initials: P
authors.lastname: Sasikumar
authors.forename: Marfoua S
authors.initials: MS
authors.lastname: Ali
authors.forename: Neline
authors.initials: N
authors.lastname: Kriek
authors.forename: Tanya
authors.initials: T
authors.lastname: Sage
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Gibbins
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D000077340:Fluvastatin; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D005229:Fatty Acids, Monounsaturated; D005343:Fibrinolytic Agents; D007211:Indoles; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000077340:Fluvastatin; D019821:Simvastatin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
references.citation: Circulation. 1998 Mar 31;97(12):1129-35
references.pmid: 9537338
references.citation: Circ Res. 2006 Feb 17;98(3):361-9
references.pmid: 16397146
references.citation: Blood. 2006 Jan 15;107(2):535-41
references.pmid: 16166583
references.citation: Cardiovasc Res. 2005 Jun 1;66(3):462-71
references.pmid: 15914111
references.citation: Vascul Pharmacol. 2007 Apr;46(4):286-92
references.pmid: 17178255
references.citation: Circulation. 2012 Jul 3;126(1):92-103
references.pmid: 22615342
references.citation: J Clin Invest. 2012 Feb;122(2):558-68
references.pmid: 22214850
references.citation: Blood. 1996 Jan 15;87(2):630-41
references.pmid: 8555485
references.citation: Atherosclerosis. 2003 Apr;167(2):187-94
references.pmid: 12818400
references.citation: Nat Rev Drug Discov. 2005 Dec;4(12):977-87
references.pmid: 16341063
references.citation: Thromb Haemost. 1999 Jun;81(6):961-6
references.pmid: 10404776
references.citation: Eur J Immunol. 1993 Oct;23(10):2464-71
references.pmid: 8405046
references.citation: J Biol Chem. 2000 Sep 1;275(35):27339-47
references.pmid: 10858437
references.citation: Nat Med. 2000 Dec;6(12):1399-402
references.pmid: 11100127
references.citation: J Immunol. 1999 Mar 1;162(5):3022-30
references.pmid: 10072554
references.citation: Br J Clin Pharmacol. 1997 Jul;44(1):77-83
references.pmid: 9241100
references.citation: Blood. 2002 Jan 1;99(1):137-44
references.pmid: 11756163
references.citation: Atherosclerosis. 2006 Sep;188(1):51-8
references.pmid: 16321392
references.citation: Blood. 2011 Apr 7;117(14):3903-6
references.pmid: 21297004
references.citation: Br J Pharmacol. 2008 Mar;153(6):1281-7
references.pmid: 18264124
references.citation: Arterioscler Thromb Vasc Biol. 2012 Nov;32(11):2609-15
references.pmid: 22995523
references.citation: Circulation. 2012 May 22;125(20):2479-91
references.pmid: 22528526
references.citation: FEBS Lett. 2009 Nov 19;583(22):3618-24
references.pmid: 19850043
references.citation: J Proteome Res. 2009 Jun;8(6):2903-14
references.pmid: 19341245
references.citation: Blood. 2011 May 26;117(21):5751-61
references.pmid: 21411760
references.citation: Arterioscler Thromb Vasc Biol. 1995 Feb;15(2):247-51
references.pmid: 7749833
references.citation: J Thromb Haemost. 2010 Nov;8(11):2530-41
references.pmid: 20723025
references.citation: Trends Immunol. 2007 Feb;28(2):88-98
references.pmid: 17197237
references.citation: Nat Med. 2001 Jun;7(6):687-92
references.pmid: 11385505
references.citation: Circulation. 2013 Jan 15;127(2):251-7
references.pmid: 23319813
references.citation: Arterioscler Thromb Vasc Biol. 2001 Jul;21(7):1165-71
references.pmid: 11451746
references.citation: N Engl J Med. 1995 Feb 23;332(8):481-7
references.pmid: 7830728
references.citation: Circulation. 2005 May 10;111(18):2356-63
references.pmid: 15867181
references.citation: J Immunol. 2001 Mar 1;166(5):3098-106
references.pmid: 11207261
references.citation: Arterioscler Thromb Vasc Biol. 2009 May;29(5):706-11
references.pmid: 19150877
references.citation: Thromb Haemost. 1999 Nov;82(5):1390-4
references.pmid: 10595624
references.citation: Blood. 2001 Mar 15;97(6):1727-32
references.pmid: 11238114
references.citation: J Immunol. 1997 Apr 1;158(7):3408-16
references.pmid: 9120301
references.citation: J Immunol. 1999 Jul 15;163(2):682-8
references.pmid: 10395658
references.citation: Pharmacol Ther. 1999 Dec;84(3):413-28
references.pmid: 10665838
references.citation: Circulation. 2002 Feb 26;105(8):933-8
references.pmid: 11864921
references.citation: Arterioscler Thromb Vasc Biol. 2002 Nov 1;22(11):1784-9
references.pmid: 12426205