Membrane Stabilizing Copolymer Poloxamer 188 in Preclinical Models of Acute Myocardial Infarction Reperfusion

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Membrane Stabilizing Copolymer Poloxamer 188 in Preclinical Models of Acute Myocardial Infarction Reperfusion

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2019-11

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Abstract

Coronary artery disease is the most common disease of the heart and number one cause of death worldwide, affecting millions annually. Acute myocardial infarction (AMI) is a classic manifestation of coronary artery disease and occurs when prolonged myocardial ischemia reaches a critical threshold, partially or completely occluding the coronary arteries, leading to necrosis of the adjacent tissue and subsequent scar formation. Despite recent advances in treatment strategies, risk of death by secondary cardiac events like hemorrhagic shock and cardiac arrest remain very high. Cellular injury after acute myocardial infarction occurs in two stages- ischemic injury, which occurs when there is a myocardial oxygen supply-demand mismatch, and reperfusion injury, which occurs with the sudden unrestrained return of blood to the oxygen deprived tissue. Some of the strategies to minimize reperfusion injury including ischemic pre-and post-conditioning, and therapeutic hypothermia have been successful in animal studies but have exhibited mixed results in clinical trials. Several cellular events that occur in ischemia including calcium overload and reactive oxygen species (ROS) generation, inflammation and myocardial contracture are further exacerbated during reperfusion injury. Mitochondria play a crucial role in augmenting the events of reperfusion injury by further increasing calcium overload, ROS induced ROS release and opening of the mitochondrial permeability transition pore, all of which triggers cell death pathways. Hence, there’s an urgent need for therapies that prevent mitochondrial dysfunction and mitigate reperfusion injury. Poloxamer 188 (P188) is the most studied member of the poloxamer family, comprised of non-ionic polymers made of a hydrophobic core, flanked by hydrophilic end chains. Due to its membrane stabilizing and anti-coagulant properties, P188 remains a favorable agent to prevent membrane damage in several disease models including sickle cell anemia, muscular dystrophy, cardiac arrest and acute myocardial infarction. The predominant theme of this dissertation revolves around understanding the events that occur at reperfusion after acute myocardial infarction and finding ways to combat this reperfusion injury with the use of P188. Here, we demonstrate for the first time the benefit of P188 administration in salvaging myocardial and mitochondrial function using a large animal model of AMI with current treatment procedures. We further investigate if this improvement in mitochondrial function transcends to the level of the two distinct mitochondrial subtypes in the heart. Finally, with the results from these studies, we examine if there’s a survival benefit with our model of AMI reperfusion. Results from this study will provide a better understanding of the events surrounding reperfusion injury within the distinctive subpopulations of mitochondria and underscore the immediate and long-lasting benefits of administering P188 promptly at reperfusion.

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University of Minnesota Ph.D. dissertation. November 2019. Major: Integrative Biology and Physiology. Advisor: Demetris Yannopoulos. 1 computer file (PDF); 161 pages.

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Chandra Shekar, Kadambari. (2019). Membrane Stabilizing Copolymer Poloxamer 188 in Preclinical Models of Acute Myocardial Infarction Reperfusion. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/218051.

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