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Principal Investigator: Nicole Collins
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $41,362
Funding agency: National Heart Lung and Blood Institute
Project Summary/Abstract
The energy utilized by the heart for contractions is primarily made by aerobic respiration. This process consists
of oxidizing carbon substrates to fuel ATP synthesis. An essential substrate is oxygen which acts as the final
electron acceptor. Without oxygen, ATP is rapidly depleted from the myocardium. There are a number of
scenarios where the heart is exposed to hypoxic or anoxic conditions. Ischemia occurs when blood flow becomes
restricted preventing oxygen delivery to part of the muscle. This occurs in ischemic heart disease. If blood flow
is not restored in time, it can lead to irreversible damage, termed myocardial infarction. Organ transplantation is
another scenario where the heart is away from blood supply during transportation. The amount of time the muscle
is without oxygen determines the health of the tissue for the recipient. Situations such as these that involve an
ischemic environment induce metabolic changes that damage the myocardium during reperfusion when oxygen
is restored, known as ischemia-reperfusion injury. One such change is succinate accumulation. During
reperfusion, the immense amount of succinate is responsible for reactive oxygen species (ROS) production that
puts oxidative stress on cardiomyocytes. Another metabolic change seen during ischemia is the depletion of
adenine nucleotides. This group includes AMP, ADP, and ATP and are all essential energy carriers in the
myocardium. The depletion of these molecules results in impaired energy metabolism in the heart. Little is known
about the mechanisms behind these metabolic changes.
The goal of this project is to uncover the primary pathways of succinate accumulation and adenine nucleotide
depletion in ischemic myocardium. The working hypothesis is the combined actions of the tricarboxylic acid
(TCA) cycle, malate-aspartate shuttle (MAS), and the purine nucleotide cycle (PNC) provide the substrate utilized
for succinate production and adenine nucleotides entering the PNC are shuttled into purine degradation
pathways. Experiments involving anoxic isolated heart mitochondrial, ischemic ex vivo hearts, and transgenic
rats will be used jointly with computational models of myocardial metabolism to test this hypothesis. The
metabolic states of these different systems will be quantified by metabolomics and enzyme inhibitors that will be
used to assess primary pathways of accumulation and depletion. Computational models will help with
experimental design, refining, and testing hypotheses. The data from this project will have applications for both
ischemic heart disease, organ transplantation, treatments for ischemia-reperfusion injury.
Terms: <2-ketoglutarate><2-oxoglutarate><5'-Inosinic acid><ATP Synthesis><ATP Synthesis Pathway><Active Oxygen><Acute><Adenine Nucleotides><Adenosine Phosphates><Anoxia><Automobile Driving><Blood flow><Body Tissues><Carbon><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac infarction><Cardiocyte><Cell Function><Cell Physiology><Cell Process><Cell Respiration><Cellular Function><Cellular Physiology><Cellular Process><Cellular Respiration><Citric Acid Cycle><Common Rat Strains><Computer Models><Computerized Models><Consumption><Data><Degradation Pathway><Degradative Pathway><Energy Expenditure><Energy Metabolism><Environment><Enzyme Antagonist><Enzyme Gene><Enzyme Inhibition><Enzyme Inhibitor><Enzyme Inhibitor Agent><Enzyme Inhibitor Drugs><Enzymes><Experimental Designs><Exposure to><Fumarate Reductase><Fumarates><Generations><Goals><Grafting Procedure><Health><Heart><Heart Mitochondria><Heart Muscle Cells><Heart myocyte><Hypoxia><Hypoxic><Impairment><Infarction><Inosine Monophosphate><Intermediary Metabolism><Ischemia><Ischemia-Reperfusion Injury><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><Ketosuccinates><Kinetics><Knock-out><Knockout><Krebs Cycle><Lead><Malate-Aspartate Shuttle Pathway><Malate-aspartate shuttle><Malates><Measurement><Metabolic><Metabolic Processes><Metabolism><Mitochondria><Modeling><Muscle><Muscle Tissue><Myocardial><Myocardial Contraction><Myocardial Infarct><Myocardial Infarction><Myocardial Ischemia><Myocardial Mitochondria><Myocardium><O element><O2 element><Organ Transplantation><Organ Transplants><Oxaloacetates><Oxidants><Oxidative Stress><Oxidizing Agents><Oxosuccinates><Oxygen><Oxygen Deficiency><Oxygen Radicals><Pathologic><Pathway interactions><Pb element><Play><Prevention><Pro-Oxidants><Process><Production><Purine Nucleotides><Purines><Rat><Rat Transgene><Rats Mammals><Rattus><Reaction><Reactive Oxygen Species><Reperfusion Damage><Reperfusion Injury><Reperfusion Therapy><Ribosylhypoxanthine Monophosphate><Role><Subcellular Process><Succinate Dehydrogenase><Succinates><Succinic Dehydrogenase><Succinic Oxidase><Suspension substance><Suspensions><System><TCA cycle><Testing><Therapeutic><Time><Tissues><Transportation><Tricarboxylic Acid Cycle><United States><Vascular blood supply><Work><acronyms><aerobic metabolism><aerobic respiration><alpha ketoglutarate><alpha-oxoglutarate><blood supply><cardiac infarct><cardiac ischemia><cardiac muscle><cardiomyocyte><computational modeling><computational models><computer based models><computer based prediction><computerized modeling><coronary attack><coronary infarct><coronary infarction><coronary ischemia><driving><electron acceptor><experiment><experimental research><experimental study><experiments><fumarate hydrogenase><heart attack><heart contraction><heart infarct><heart infarction><heart ischemia><heart muscle><heavy metal Pb><heavy metal lead><improved><infarct><metabolism measurement><metabolomics><metabonomics><mitochondrial><muscular><myocardial damage><myocardial ischemia/hypoxia><myocardium ischemia><organ allograft><organ graft><organ xenograft><oxidative metabolism><pathway><predictive modeling><prevent><preventing><reperfusion><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><vascular supply><α-ketoglutarate><α-oxoglutarate><αKG>