title: Inhibition of the Renin-Angiotensin System Post Myocardial Infarction Prevents Inflammation-Associated Acute Cardiac Rupture.
abstract: OBJECTIVE
  Inhibition of the renin-angiotensin system (RAS) is beneficial in patient management after myocardial infarction (MI). However, whether RAS inhibition also provides cardiac protection in the acute phase of MI is unclear.
  
  
  METHODS
  Male 129sv mice underwent coronary artery occlusion to induce MI, followed by treatment with losartan (L, 20 and 60 mg/kg), perindopril (P, 2 and 6 mg/kg), amlodipine (20 mg/kg as a BP-lowering agent) or vehicle as control. Drug effects on hemodynamics were examined. Effects of treatments on incidence of cardiac rupture, haematological profile, monocyte and neutrophil population in the spleen and the heart, cardiac leukocyte density, expression of inflammatory genes and activity of MMPs were studied after MI.
  
  
  RESULTS
  Incidence of cardiac rupture within 2 weeks was significantly and similarly reduced by both losartan (L) and perindopril (P) in a dose-dependent manner [75% (27/36) in vehicle, 40-45% in low-dose (L 10/22, P 8/20) and 16-20% (L 5/32, P 4/20) in high-dose groups, all P < 0.05]. This action was independent of their BP-lowering action, as amlodipine reduced BP to a similar degree without effect on rupture (70%, 21/30). Compared to the control group, high dose losartan and perindopril decreased counts of white blood cells, neutrophils and lymphocytes (all P < 0.05), and inhibited splenic monocyte and neutrophil release into the circulation. Consequently, monocyte, neutrophil and leukocyte infiltration, inflammatory gene expressions (IL-1β, IL-6, MMP9, MCP-1, TNF-α and TGFβ1) and activity of MMP2 and MMP9 in the infarct tissue were attenuated by losartan and/or perindopril treatment (all P < 0.05).
  
  
  CONCLUSIONS
  RAS inhibition by losartan or perindopril prevented cardiac rupture at the acute phase of MI through blockade of splenic release of monocytes and neutrophils and consequently attenuation of systemic and regional inflammatory responses.
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004, VIC, Australia. xiaoming.gao@bakeridi.edu.au.|Department of Surgery, Central Clinical School, Monash University, Melbourne, Australia. xiaoming.gao@bakeridi.edu.au.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Gao
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004, VIC, Australia.
authors.forename: Alan
authors.initials: A
authors.lastname: Tsai
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004, VIC, Australia.
authors.forename: Annas
authors.initials: A
authors.lastname: Al-Sharea
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004, VIC, Australia.
authors.forename: Yidan
authors.initials: Y
authors.lastname: Su
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004, VIC, Australia.
authors.forename: Shirley
authors.initials: S
authors.lastname: Moore
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004, VIC, Australia.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Han
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004, VIC, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004, VIC, Australia.|Alfred Heart Centre, Alfred Hospital, Melbourne, Australia.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Dart
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004, VIC, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004, VIC, Australia. xiao-jun.du@bakeridi.edu.au.|Department of Medicine, Central Clinical School, Monash University, Melbourne, Australia. xiao-jun.du@bakeridi.edu.au.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
mesh_terms: D017311:Amlodipine / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006342:Heart Rupture, Post-Infarction / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D057507:Mice, 129 Strain; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D020913:Perindopril / Q000494:pharmacology*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D016207:Cytokines; D018836:Inflammation Mediators; D017311:Amlodipine; D019808:Losartan; D020913:Perindopril
keywords: ACE inhibitor; AT1 receptor blocker; Cardiac rupture; Inflammation; Myocardial infarction; Renin-angiotensin system