Cardioprotective Effects of HSP72 Administration on Ischemia-Reperfusion Injury

Takashi Tanimoto, Missag H. Parseghian, Takehiro Nakahara, Hideki Kawai, Navneet Narula, Dongbin Kim, Robert Nishimura, Richard H. Weisbart, Grace Chan, Richard A. Richieri, Nezam Haider, Farhan Chaudhry, Glenn T. Reynolds, John Billimek, Francis G. Blankenberg, Partho P. Sengupta, Artiom D. Petrov, Takashi Akasaka, H. William Strauss, Jagat Narula

研究成果: Article

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Background Although early reperfusion is the most desirable intervention after ischemic myocardial insult, it may add to damage through oxidative stress. Objectives This study investigated the cardioprotective effects of a single intravenous dose of heat shock protein-72 (HSP72) coupled to a single-chain variable fragment (Fv) of monoclonal antibody 3E10 (3E10Fv) in a rabbit ischemia-reperfusion model. The Fv facilitates rapid transport of HSP72 into cells, even with intact membranes. Methods A left coronary artery occlusion (40 min) reperfusion (3 h) model was used in 31 rabbits. Of these, 12 rabbits received the fusion protein (Fv-HSP72) intravenously. The remaining 19 control rabbits received a molar equivalent of 3E10Fv alone (n = 6), HSP72 alone (n = 6), or phosphate-buffered saline (n = 7). Serial echocardiographic examinations were performed to assess left ventricular function before and after reperfusion. Micro–single-photon emission computed tomography imaging of 99mTc-labeled annexin-V was performed with micro–computed tomography scanning to characterize apoptotic damage in vivo, followed by gamma counting of the excised myocardial specimens to quantify cell death. Histopathological characterization of the myocardial tissue and sequential cardiac troponin I measurements were also undertaken. Results Myocardial annexin-V uptake was 43% lower in the area at risk (p = 0.0003) in Fv-HSP72–treated rabbits compared with control animals receiving HSP72 or 3E10Fv alone. During reperfusion, troponin I release was 42% lower and the echocardiographic left ventricular ejection fraction 27% higher in the Fv-HSP72–treated group compared with control animals. Histopathological analyses confirmed penetration of 3E10Fv-containing molecules into cardiomyocytes in vivo, and treatment with Fv-HSP72 showed fewer apoptotic nuclei compared with control rabbits. Conclusions Single-dose administration of Fv-HSP72 fusion protein at the time of reperfusion reduced myocardial apoptosis by almost one-half and improved left ventricular functional recovery after myocardial ischemia-reperfusion injury in rabbits. It might have potential to serve as an adjunct to early reperfusion in the management of myocardial infarction.

元の言語English
ページ(範囲)1479-1492
ページ数14
ジャーナルJournal of the American College of Cardiology
70
発行部数12
DOI
出版物ステータスPublished - 19-09-2017
外部発表Yes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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    Tanimoto, T., Parseghian, M. H., Nakahara, T., Kawai, H., Narula, N., Kim, D., Nishimura, R., Weisbart, R. H., Chan, G., Richieri, R. A., Haider, N., Chaudhry, F., Reynolds, G. T., Billimek, J., Blankenberg, F. G., Sengupta, P. P., Petrov, A. D., Akasaka, T., Strauss, H. W., & Narula, J. (2017). Cardioprotective Effects of HSP72 Administration on Ischemia-Reperfusion Injury. Journal of the American College of Cardiology, 70(12), 1479-1492. https://doi.org/10.1016/j.jacc.2017.07.762