Effect Of Membrane Sealing Copolymer Poloxamer188 On Cardiac Mitochondrial Subpopulations In A Porcine Model Of Acute Myocardial Infarction
Authors: Shekar Kadambari Chandra , McKnite Scott , Matsuura Timothy , Olocco Matthew , Sebastian Pierre , Bartos Jason , Vuda Madhusudanarao , Rees Jennifer , Yannopoulos Demetris 
Published: June 2021

Acute myocardial infarction (AMI) is characterized by the sudden loss of blood supply to the coronary arteries, leading to permanent cell death if left untreated. Every year, around 800,000 Americans are affected by AMI. Currently, the only successful treatment for AMI is the restoration of blood flow using angioplasty and fibrinolytic drugs. In spite of a higher success rate post treatment, AMI greatly increases the risk of future arrhythmia, stroke and cardiac arrest. Additionally, the abrupt reintroduction of oxygen to the ischemic tissue causes reperfusion injury (RI). In the mitochondria, RI leads to calcium overload, increased ROS production, opening of mitochondrial permeability transition pore (MPTP) and release of caspases, all contributing to cell death. Hence, mitochondria offer a promising target in reducing reperfusion injury post AMI. Previously, we showed that the administration of the membrane sealing copolymer Poloxamer188 (P188) post ST‐elevation myocardial infarction (STEMI) reperfusion reduced infarct size and improved cardiac myocardial and mixed mitochondrial function in pigs. In this current study, our aim was to identify the specific effects of P188 in improving the mitochondrial function post STEMI of the two cardiac mitochondrial subpopulations‐subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria. Female pigs that underwent 45 minutes of partial left anterior descending artery (LAD) occlusion were randomized to be reperfused with P188 (250 mg/kg, n=5) or saline(n=5). Each of these animals received an initial intracoronary bolus of either drug for 30 minutes, followed by an intravenous drip of the same dose for 3 hours. At 4 hours post reperfusion, the hearts were harvested and cardiac SSM and IFM were isolated from both the ischemic (LAD) and healthy circumflex (Circ) area through differential centrifugation. Their functions were assessed by measuring mitochondrial oxygen consumption and calcium buffering capacity. Initial results show that P188 likely improved complex 1 mediated mitochondrial oxygen consumption in the SSM (not significant) while there was no effect on IFM. P188 also improved the calcium buffering capacity of cardiac SSM and IFM (p=0.009 for SSM and p=0.03 for IFM) in the ischemic area. Together these results show a potential treatment benefit of P188 on cardiac SSM. Future studies include measurement of the levels of reactive oxygen species and total calcium content in the mitochondria, assessment of mitochondrial damage through electron microscopy as well as investigation of the mechanism of benefit conferred by P188 in the mitochondria. To our knowledge, this is the first study to investigate the effect of P188 in cardiac mitochondrial subpopulations. Results from this study will help in the development of better targeted compounds with greater accuracy for the treatment of heart disease.Support or Funding InformationSource of funding: National Institutes of Heath, RO1 HL122323‐01A1This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.