title: Combined treatment with bexarotene and rosuvastatin reduces angiotensin-II-induced abdominal aortic aneurysm in apoE(-/-) mice and angiogenesis.
abstract: OBJECTIVE
  Abdominal aortic aneurysm (AAA) is a degenerative vascular disease associated with angiogenesis. Bexarotene is a retinoid X receptor (RXR) ligand with anti-angiogenic activity. Statins also exert anti-angiogenic activity and activate PPARs. Because RXR ligands form permissive heterodimers with PPARs and a single anti-angiogenic drug may not be sufficient to combat the wide array of angiogenic factors produced during AAA, we evaluated the effect of combined low doses of bexarotene and rosuvastatin in a mouse model of AAA.
  
  
  METHODS
  The effect of the combined treatment was investigated in a murine model of angiotensin II-induced AAA in apoE(-/-) mice. This combination therapy was also evaluated in in vivo (Matrigel plug assay) and in vitro (endothelial cell differentiation assay) models of angiogenesis as well as the underlying mechanisms involved.
  
  
  RESULTS
  Co-treatment with bexarotene plus rosuvastatin reduced aneurysm formation, inflammation and neovascularization compared with each single treatment. In HUVEC, the combination of suboptimal concentrations of bexarotene and rosuvastatin inhibited angiotensin II-induced morphogenesis, proliferation and migration. These effects were accompanied by diminished production of pro-angiogenic chemokines (CXCL1, CCL2 or CCL5) and VEGF, and seemed to be mediated by RXRα/PPARα and RXRα/PPARγ activation. This combined therapy reduced the activation of members of the downstream PI3K pathway (Akt/mTOR and p70S6K1) in vivo and in vitro.
  
  
  CONCLUSIONS
  The combination of RXR agonists with statins at low doses synergistically interferes with the signalling pathways that modulate inflammation and angiogenesis and may constitute a new and safer therapeutic treatment for the control of AAA.
authors: Institute of Health Research-INCLIVA, Valencia, Spain.|Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain.
authors: P
authors: P
authors: Escudero
authors: Institute of Health Research-INCLIVA, Valencia, Spain.
authors: A
authors: A
authors: Navarro
authors: Institute of Health Research-INCLIVA, Valencia, Spain.|Anethesiology Unit, University Clinic Hospital of Valencia, Valencia, Spain.
authors: C
authors: C
authors: Ferrando
authors: Institute of Health Research-INCLIVA, Valencia, Spain.
authors: E
authors: E
authors: Furio
authors: Institute of Health Research-INCLIVA, Valencia, Spain.
authors: H
authors: H
authors: Gonzalez-Navarro
authors: Cardiovascular Surgery Unit, University Clinic Hospital of Valencia, Valencia, Spain.
authors: M
authors: M
authors: Juez
authors: Institute of Health Research-INCLIVA, Valencia, Spain.|Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain.
authors: M J
authors: MJ
authors: Sanz
authors: Institute of Health Research-INCLIVA, Valencia, Spain.
authors: L
authors: L
authors: Piqueras
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000235:genetics*; D000077610:Bexarotene; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000068718:Rosuvastatin Calcium / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D001057:Apolipoproteins E; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013764:Tetrahydronaphthalenes; D000804:Angiotensin II; D000068718:Rosuvastatin Calcium; D000077610:Bexarotene; D019869:Phosphatidylinositol 3-Kinases
references: Arterioscler Thromb Vasc Biol. 2006 Sep;26(9):2077-82
references: 16809548
references: Ann Vasc Surg. 2011 Feb;25(2):229-39
references: 21131172
references: Br J Pharmacol. 2012 Jan;165(2):373-9
references: 21790534
references: Nat Rev Mol Cell Biol. 2008 Jul;9(7):517-31
references: 18568040
references: J Biol Chem. 1999 Mar 26;274(13):9116-21
references: 10085162
references: Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2605-13
references: 16973970
references: PLoS One. 2013;8(3):e59233
references: 23555637
references: Int J Clin Pharmacol Ther. 2007 Jun;45(6):319-27
references: 17595889
references: Hum Mol Genet. 2010 May 15;19(10):1908-20
references: 20159776
references: Expert Opin Pharmacother. 2008 Aug;9(12):2145-60
references: 18671469
references: Arterioscler Thromb Vasc Biol. 2009 Nov;29(11):1764-71
references: 19729613
references: Br J Pharmacol. 2010 Mar;159(6):1294-303
references: 20136831
references: Circ Res. 2002 Jul 26;91(2):143-50
references: 12142347
references: Vasc Med. 2002 Feb;7(1):45-54
references: 12083734
references: J Immunol. 2006 May 1;176(9):5577-86
references: 16622027
references: Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2731-7
references: 17008586
references: Med Sci Monit. 2007 Jun;13(6):RA87-90
references: 17534244
references: Am J Cardiovasc Drugs. 2008;8(6):373-418
references: 19159124
references: Pharmacol Res. 2014 Oct;88:12-9
references: 24631782
references: Am J Physiol Heart Circ Physiol. 2004 Sep;287(3):H1232-8
references: 15317677
references: Lab Invest. 2002 Jun;82(6):747-56
references: 12065685
references: J Pharm Sci. 2009 May;98(5):1877-84
references: 18803263
references: Br J Cancer. 2006 Mar 13;94(5):654-60
references: 16495926
references: Cell Mol Life Sci. 2003 Apr;60(4):810-9
references: 12785728
references: Br J Dermatol. 2013 Jan;168(1):192-200
references: 22963233
references: Br J Pharmacol. 2013 Dec;170(8):1459-581
references: 24517644
references: Thromb Res. 2013 Mar;131(3):268-76
references: 23276528
references: Arterioscler Thromb Vasc Biol. 2007 Jan;27(1):63-9
references: 17068288
references: Br J Pharmacol. 2013 Dec;170(8):1676-705
references: 24528241
references: Nucleic Acids Res. 2014 Jan;42(Database issue):D1098-106
references: 24234439
references: Am J Physiol Endocrinol Metab. 2012 Jan 15;302(2):E201-8
references: 22028412
references: Eur Urol. 2010 Sep;58(3):418-26
references: 20605315
references: Science. 2012 Mar 23;335(6075):1503-6
references: 22323736
references: Cell Death Differ. 2004 Dec;11 Suppl 2:S126-43
references: 15608692
references: Br J Pharmacol. 2010 Aug;160(7):1577-9
references: 20649561
references: Atherosclerosis. 2006 Sep;188(1):51-8
references: 16321392
references: Br J Pharmacol. 2013 Dec;170(8):1797-867
references: 24528243
references: J Vasc Surg. 2007 Mar;45(3):574-80
references: 17321344
references: Clin Cancer Res. 2007 May 15;13(10):2825-30
references: 17504979
references: Circ Res. 2011 Apr 15;108(8):1002-16
references: 21493923
references: Nature. 2008 Jul 24;454(7203):436-44
references: 18650914
references: J Cardiovasc Pharmacol Ther. 2013 Jul;18(4):327-33
references: 23364255
references: J Vasc Surg. 2004 Aug;40(2):334-8
references: 15297830
references: Curr Opin Pharmacol. 2013 Apr;13(2):260-4
references: 23402735
references: Clinics (Sao Paulo). 2011;66(8):1457-62
references: 21915500
references: Nat Rev Immunol. 2002 Sep;2(9):664-74
references: 12209135
references: J Exp Med. 2014 Mar 10;211(3):395-404
references: 24516119
references: Br J Pharmacol. 2010 Aug;160(7):1573-6
references: 20649560
references: J Biol Chem. 2008 Nov 21;283(47):32562-9
references: 18790741
references: Ann N Y Acad Sci. 2006 Nov;1085:82-91
references: 17182925
references: Mol Cancer Ther. 2005 May;4(5):824-34
references: 15897247
references: Clin Sci (Lond). 2011 Apr;120(8):307-19
references: 21488224
references: J Immunol. 2012 Jul 1;189(1):411-24
references: 22661092
references: PLoS One. 2013 Oct 01;8(10):e76541
references: 24098526
references: Br J Pharmacol. 2013 Dec;170(8):1652-75
references: 24528240
references: Angiogenesis. 2012 Dec;15(4):727-44
references: 22752444
references: Int Angiol. 2010 Jun;29(3):260-5
references: 20502414
references: Mol Pharmacol. 2006 Jul;70(1):415-25
references: 16611854
references: BMJ. 2013 Mar 18;346:f880
references: 23511950
references: Front Mol Neurosci. 2011 Dec 02;4:51
references: 22144946
references: Atherosclerosis. 2011 Jul;217(1):90-6
references: 21481872
references: PLoS One. 2012;7(1):e28305
references: 22279523
references: Circulation. 2004 Dec 7;110(23):3581-6
references: 15569833