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Relaxin mitigates microvascular damage and inflammation following cardiac ischemia–reperfusion

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Abstract

Microvascular obstruction (MVO) and leakage (MVL) forms a pivotal part of microvascular damage following cardiac ischemia–reperfusion (IR). We tested the effect of relaxin therapy on MVO and MVL in mice following cardiac IR injury including severity of MVO and MVL, opening capillaries, infarct size, regional inflammation, cardiac function and remodelling, and permeability of cultured endothelial monolayer. Compared to vehicle group, relaxin treatment (50 μg/kg) reduced no-reflow area by 38% and the content of Evans blue as a permeability tracer by 56% in jeopardized myocardium (both P < 0.05), effects associated with increased opening capillaries. Relaxin also decreased leukocyte density, gene expression of cytokines, and mitigated IR-induced decrease in protein content of VE-cadherin and relaxin receptor. Infarct size was comparable between the two groups. At 2 weeks post-IR, relaxin treatment partially preserved cardiac contractile function and limited chamber dilatation versus untreated controls by echocardiography. Endothelial cell permeability assay demonstrated that relaxin attenuated leakage induced by hypoxia-reoxygenation, H2O2, or cytokines, action that was independent of nitric oxide but associated with the preservation of VE-cadherin. In conclusion, relaxin therapy attenuates IR-induced MVO and MVL and endothelial leakage. This protection was associated with reduced regional inflammatory responses and consequently led to alleviated adverse cardiac remodeling.

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Acknowledgements

This study was funded by Grants (ID1081710, ID1005329) from the National Health and Medical Research Council (NHMRC) of Australia, the Victorian Government’s Operational Infrastructure Support Program, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asian, China (SKL-HIDCA-2017-Y11) and Nature Science Foundation of Xinjiang (2018D01C197). XJD was NHMRC research fellow (ID1043026). The authors acknowledge Novartis AG for supply of test sample of relaxin. We acknowledge a development grant provided by the Heini Foundations.

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Authors and Affiliations

  1. Experimental Cardiology Laboratory, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia

    Xiao-Ming Gao, Yidan Su, Shirley Moore, Li-Ping Han, Helen Kiriazis, Qun Lu, Wei-Bo Zhao & Xiao-Jun Du

  2. State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Ürümqi, China

    Xiao-Ming Gao, Amanguli Ruze, Bin-Bin Fang & Ming-Jun Duan

  3. Xinjiang Key Laboratory of Medical Animal Model Research, Clinical Medical Research Institute of Xinjiang Medical University, Ürümqi, China

    Xiao-Ming Gao, Amanguli Ruze, Bin-Bin Fang & Ming-Jun Duan

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

    Xiao-Ming Gao

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Gao, XM., Su, Y., Moore, S. et al. Relaxin mitigates microvascular damage and inflammation following cardiac ischemia–reperfusion. Basic Res Cardiol 114, 30 (2019). https://doi.org/10.1007/s00395-019-0739-9

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