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Inhibition of the Renin-Angiotensin System Post Myocardial Infarction Prevents Inflammation-Associated Acute Cardiac Rupture

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Abstract

Purpose

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.

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Authors and Affiliations

  1. Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004, VIC, Australia

    Xiao-Ming Gao, Alan Tsai, Annas Al-Sharea, Yidan Su, Shirley Moore, Li-Ping Han, Helen Kiriazis, Anthony M. Dart, Andrew J. Murphy & Xiao-Jun Du

  2. Department of Surgery, Central Clinical School, Monash University, Melbourne, Australia

    Xiao-Ming Gao

  3. Alfred Heart Centre, Alfred Hospital, Melbourne, Australia

    Anthony M. Dart

  4. Department of Medicine, Central Clinical School, Monash University, Melbourne, Australia

    Xiao-Jun Du

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  1. Xiao-Ming Gao
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Corresponding authors

Correspondence to Xiao-Ming Gao or Xiao-Jun Du.

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Funding

This study was funded by grants (ID 1081710, 1004235) from the National Health and Medical Research Council (NHMRC) of Australia and the Victorian Government’s Operational Infrastructure Support Program. A.J.M. is supported by a career development fellowship from the NHMRC (ID1085752), a future leader fellowship from the National Heart Foundation (ID100440). X.J.D. and A.M.D are NHMRC research fellow (ID1043026 and ID586656).

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

The mouse was used in this study. All experimental protocols were approved by a local Animal Ethics Committee and complied with the Australian Code for the Care and Use of Animals for Scientific Purposes (8th edition, 2013).

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Gao, XM., Tsai, A., Al-Sharea, A. et al. Inhibition of the Renin-Angiotensin System Post Myocardial Infarction Prevents Inflammation-Associated Acute Cardiac Rupture. Cardiovasc Drugs Ther 31, 145–156 (2017). https://doi.org/10.1007/s10557-017-6717-2

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  • DOI: https://doi.org/10.1007/s10557-017-6717-2

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