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Effects of OP2113 on Myocardial Infarct Size and No Reflow in a Rat Myocardial Ischemia/Reperfusion Model

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Abstract

Purpose

The present study was to determine whether OP2113 could limit myocardial infarction size and the no-reflow phenomenon in a rat myocardial ischemia/reperfusion model.

Methods

Rat heart–isolated mitochondria (RHM) were used to investigate mitochondrial respiration and mitochondrial reactive oxygen species (mtROS) generation both in normal conditions and in ischemia/reperfusion-mimicking conditions (using high concentrations of succinate). Human skeletal muscle myoblasts (HSMM) in culture were used to investigate the cellular intermittent deprivation in energy substrates and oxygen as reported in ischemia/reperfusion conditions. In vivo, rats were anesthetized and subjected to 30 min of left coronary artery occlusion followed by 3 h of reperfusion. Rats were randomized to receive OP2113 as an intravenous infusion starting either 5 min prior to coronary artery occlusion (preventive), or 5 min prior to reperfusion (curative), or to receive vehicle starting 5 min prior to coronary artery occlusion. Infusions continued until the end of the study (3 h of reperfusion).

Results

RHM treated with OP2113 showed a concentration-dependent reduction of succinate-induced mtROS generation. In HSMM cells, OP2113 treatment (5–10 μM) during 48H prevented the reduction in the steady-state level of ATP measured just after reperfusion injuries and decreased the mitochondrial affinity to oxygen. In vivo, myocardial infarct size, expressed as the percentage of the ischemic risk zone, was significantly lower in the OP2113-treated preventive group (44.5 ± 2.9%) versus that in the vehicle group (57.0 ± 3.6%; p < 0.05), with a non-significant trend toward a smaller infarct size in the curative group (50.8 ± 3.9%). The area of no reflow as a percentage of the risk zone was significantly smaller in both the OP2113-treated preventive (28.8 ± 2.4%; p = 0.026 vs vehicle) and curative groups (30.1 ± 2.3%; p = 0.04 vs vehicle) compared with the vehicle group (38.9 ± 3.1%). OP2113 was not associated with any hemodynamic changes.

Conclusions

These results suggest that OP2113 is a promising mitochondrial ROS–modulating agent to reduce no-reflow as well as to reduce myocardial infarct size, especially if it is on board early in the course of the infarction. It appears to have benefit on no-reflow even when administered relatively late in the course of ischemia.

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Funding

Dr. Robert A. Kloner is the principle investigator of this work, and the project was supported by OP2 Drugs, Pessac, France.

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Authors and Affiliations

  1. HMRI Cardiovascular Research Institute, Huntington Medical Research Institutes, 686 S. Fair Oaks Avenue, Pasadena, CA, 91105, USA

    Wangde Dai, Juan Carreno, Lifu Zhao & Robert A. Kloner

  2. Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    Wangde Dai & Robert A. Kloner

  3. Cellomet, Bordeaux, France

    Nivea Dias Amoedo & Rodrigue Rossignol

  4. Virginia Polytechnic Institute and State University, 1035 ILSB, 1981 Kraft Drive, Virginia Tech Corporate Research Center, Blacksburg, VA, 24060, USA

    Justin Perry & David A. Brown

  5. OP2 Drugs, Pessac, France

    Bruno Le Grand & Aurelie Boucard

  6. INSERM U1211, Bordeaux, France

    Rodrigue Rossignol

Authors
  1. Wangde Dai
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  2. Nivea Dias Amoedo
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  3. Justin Perry
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  7. Lifu Zhao
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  10. Robert A. Kloner
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Contributions

The authors made substantial contributions to the conception or design of the work (R.A.K.) or to the acquisition, analysis, or interpretation of data for the work (W.D., N.D.A., J.P., B.L.G., A.B., J.C., L.Z., D.A.B., R.R., R.A.K.); participated in critically revising the manuscript (W.D., N.D.A., J.P., B.L.G., A.B., J.C., L.Z., D.A.B., R.R., R.A.K.); approved the final version to be published (W.D., N.D.A., J.P., B.L.G., A.B., J.C., L.Z., D.A.B., R.R., R.A.K.); and agreed to be accountable for all aspects of the work (W.D., N.D.A., J.P., B.L.G., A.B., J.C., L.Z., D.A.B., R.R., R.A.K.).

Corresponding author

Correspondence to Wangde Dai.

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Conflict of Interest

Aurélie Boucard and Bruno Le Grand are employees for OP2 Drugs. Rodrigue Rossignol is a scientific advisor for OP2 Drugs. There are no conflicts of interest for Drs. Dai, Amoedo, Perry, Carreno, Zhao, Brown, and Kloner.

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Dai, W., Amoedo, N.D., Perry, J. et al. Effects of OP2113 on Myocardial Infarct Size and No Reflow in a Rat Myocardial Ischemia/Reperfusion Model. Cardiovasc Drugs Ther 36, 217–227 (2022). https://doi.org/10.1007/s10557-020-07113-7

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