title: Combination therapy with atorvastatin and amlodipine suppresses angiotensin II-induced aortic aneurysm formation.
abstract: BACKGROUND
  Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. It is controversial whether statin and calcium channel blockers (CCBs) has an inhibitory effect on the expansion of AAA. Some studies reported that CCBs have an inhibitory effect on Rho-kinase activity. Rho-kinase plays an important role in the pathogenesis of various cardiovascular diseases. However, there is no study reporting of the association between Rho-kinase and human AAAs.
  
  
  RESULTS
  Experimental AAA was induced in Apolipoprotein E-deficient (ApoE(-/-)) mice infused with angiotensin II (AngII) for 28 days. They were randomly divided into the following 5 groups; saline infusion alone (sham), AngII infusion alone, AngII infusion plus atorvastatin (10 mg/kg/day), AngII infusion plus amlodipine (1 mg/kg/day), and AngII infusion plus combination therapy with atorvastatin (10 mg/kg/day) and amlodipine (1 mg/kg/day). The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy significantly reduced AngII-induced apoptosis and elastin degradation at the AAA lesion, whereas each monotherapy did not. Moreover, Rho-kinase activity, as evaluated by the extent of phosphorylation of myosin-binding subunit (a substrate of Rho-kinase) and matrix metalloproteinase activity were significantly increased in the AngII-induced AAA lesion as compared with sham, both of which were again significantly suppressed by the combination therapy. In human aortic samples, immunohistochemistory revealed that the activity and expression of Rho-kinase was up-regulated in AAA lesion as compared with abdominal aorta from control subjects.
  
  
  CONCLUSIONS
  Rho-kinase is up-regulated in the aortic wall of human AAA. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which Rho-kinase inhibition may be involved.
authors: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Kikuyo
authors: K
authors: Takahashi
authors: Yasuharu
authors: Y
authors: Matsumoto
authors: Zhulanqiqige
authors: Z
authors: Do e
authors: Masanori
authors: M
authors: Kanazawa
authors: Kimio
authors: K
authors: Satoh
authors: Takuya
authors: T
authors: Shimizu
authors: Akira
authors: A
authors: Sato
authors: Yoshihiro
authors: Y
authors: Fukumoto
authors: Hiroaki
authors: H
authors: Shimokawa
mesh_terms: D017311:Amlodipine / Q000008:administration & dosage / Q000494:pharmacology*; D000804:Angiotensin II / Q000009:adverse effects; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D000069059:Atorvastatin; D001794:Blood Pressure; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004789:Enzyme Activation; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D008055:Lipids / Q000097:blood; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011758:Pyrroles; D000804:Angiotensin II; D017311:Amlodipine; D000069059:Atorvastatin; D054460:rho-Associated Kinases; D020782:Matrix Metalloproteinases
references: Circ Res. 2007 Jun 22;100(12):1686-95
references: 17585076
references: Circ Res. 2008 Jun 6;102(11):1368-77
references: 18451339
references: Vasc Endovascular Surg. 2010 Feb;44(2):116-22
references: 20034937
references: Circ J. 2009 Sep;73(9):1731-9
references: 19590140
references: Circ J. 2009 Feb;73(2):361-70
references: 19060417
references: Cardiovasc Res. 2011 Jul 15;91(2):358-67
references: 21436157
references: Nat Rev Cardiol. 2009 Aug;6(8):543-52
references: 19546866
references: Vascul Pharmacol. 2010 Jul-Aug;53(1-2):11-21
references: 20347049
references: J Hypertens. 2011 Feb;29(2):373-9
references: 21063203
references: J Vasc Surg. 2012 Jun;55(6):1593-9
references: 22503181
references: Eur Heart J. 2009 Feb;30(3):346-55
references: 19010796
references: Br J Surg. 2011 Mar;98(3):346-53
references: 21254006
references: J Vasc Surg. 2010 Jul;52(1):1-4
references: 20494541
references: Drug Metab Dispos. 1998 Aug;26(8):755-63
references: 9698289
references: PLoS One. 2012;7(11):e44369
references: 23209546
references: Cardiovasc Res. 2011 Apr 1;90(1):18-27
references: 21037321
references: Am J Physiol Heart Circ Physiol. 2009 May;296(5):H1660-5
references: 19252100
references: Am J Cardiol. 2006 Jan 15;97(2):279-80
references: 16442379
references: PLoS One. 2012;7(4):e35312
references: 22514726
references: Circulation. 2005 May 3;111(17):2219-26
references: 15851596
references: Circ Res. 2006 Mar 31;98(6):811-7
references: 16527992
references: Arterioscler Thromb Vasc Biol. 2005 Sep;25(9):1767-75
references: 16002741
references: Am J Physiol Heart Circ Physiol. 2011 Aug;301(2):H287-96
references: 21622831
references: J Cardiovasc Pharmacol. 2003 Jul;42(1):118-24
references: 12827036
references: Nat Med. 2009 Jun;15(6):649-56
references: 19430489
references: Brain Res. 2011 Mar 25;1382:308-14
references: 21276424
references: Hypertension. 2010 Apr;55(4):918-23
references: 20194307
references: Clin Pharmacol Ther. 1996 Dec;60(6):687-95
references: 8988072
references: J Clin Invest. 2003 Nov;112(9):1318-31
references: 14597759
references: Cardiovasc Res. 2008 Dec 1;80(3):346-53
references: 18687705
references: Circ Res. 2009 Jul 17;105(2):167-75
references: 19520970
references: Circulation. 2008 Apr 8;117(14):1883-9
references: 18391122
references: J Clin Invest. 2010 Feb;120(2):422-32
references: 20101093
references: Circ J. 2010 May;74(5):818-26
references: 20424337
references: Circulation. 2010 Feb 16;121(6):759-67
references: 20124122
references: Nat Rev Cardiol. 2011 Feb;8(2):92-102
references: 21079638
references: Atherosclerosis. 2011 Jul;217(1):57-63
references: 21596379
references: J Vasc Surg. 2010 Jul;52(1):55-61.e2
references: 20620765
references: J Am Coll Surg. 2009 Jul;209(1):41-6
references: 19651061
references: Hypertension. 2010 May;55(5):1267-74
references: 20212272
references: Hypertens Res. 2011 Apr;34(4):450-5
references: 21270816
references: J Cardiovasc Pharmacol. 1988;12 Suppl 7:S55-9
references: 2467130
references: Atherosclerosis. 2011 Jul;217(1):90-6
references: 21481872
references: Cardiovasc Res. 2009 Aug 1;83(3):436-43
references: 19454489