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Principal Investigator: Alan J Mouton
Organization: UNIVERSITY OF MISSISSIPPI MED CTR
Fiscal Year: 2024
Award: $584,122
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY/ABSTRACT
Approximately 1 million people in the United States suffer a myocardial infarction (MI) each year, leading to
progressive cardiac dysfunction and development of heart failure (HF) in ~25% of surviving patients. Diabetes
mellitus is a major risk factor for MI, and patients with diabetes suffer from higher mortality rates and increased
risk of developing HF. Due to the limited success of current therapies in preventing adverse cardiac remodeling
after MI, novel therapeutic targets are needed to effectively promote adequate healing and limit tissue damage,
especially in diabetic patients. Excessive macrophage-mediated inflammation is a key mechanism leading to
adverse cardiac remodeling after MI, and patients with diabetes display exacerbated and persistent post-MI
inflammatory responses. A key mechanism by which macrophages polarize between the pro-inflammatory “M1”
and anti-inflammatory/pro-reparative “M2” subsets is via metabolic reprogramming characterized by phenotypic
switches between glycolytic metabolism, which promotes M1 polarization, and mitochondrial oxidative
phosphorylation (OXPHOS), which promotes M2 polarization. Using Seahorse metabolic flux analysis, I have
found that during the early inflammatory phase (day 1 and 3 after MI in mice), infarct macrophages become
glycolytic, whereas during the healing phase (day 7), macrophages revert to glucose oxidation and OXPHOS. In
addition to glucose, macrophages can metabolize “alternative” fuels, including lactate and ketone bodies, which
promote an M2 phenotype. However, the role of lactate and ketone body metabolism by macrophages during
MI is unknown, and whether administration or endogenous production of these compounds can promote M2
macrophage polarization during MI is also not known. My preliminary data indicate that expression of genes
related to lactate (Mct1, Ldhb) and ketone (Oxct1) metabolism are upregulated in macrophage during the wound
healing phase of MI. Further preliminary data indicates that in vivo administration of lactate or ketones, or feeding
a ketogenic diet attenuates the macrophage immunometabolic phenotype after MI. This indicates that
metabolism of these substrates may underlie M2 polarization and cardiac healing after MI. Thus, the hypothesis
for this proposal is that elevated endogenous production or exogenous administration of lactate and
ketones will improve cardiac remodeling and reduces cardiac injury after MI via improved macrophage
metabolism and polarization. I also propose that diabetes exacerbates MI injury via impaired
macrophage lactate and ketone metabolism. To address these hypotheses, I will use clinically relevant mouse
models of MI and diabetes mellitus, and macrophage-specific genetically modified mice, coupled with state-of-
the-art techniques for measuring cardiac function (high resolution ultrasound echocardiography and 4D imaging),
live cellular metabolism, macrophage isolation by immunomagnetic sorting, and flow cytometry. These studies
will provide new mechanisms of lactate and ketone-mediated cardioprotection, and novel strategies for targeting
macrophage metabolism following cardiac injury.
Terms: <21+ years old><3 Hydroxybutyrate><4-D imaging><4D Imaging><Acetoacetates><Address><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Affect><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatory Effect><Area><Attenuated><Automobile Driving><Beta Proprotein Interleukin 1><Body Tissues><Carbohydrates><Cardiac><Cardiac artery><Cardiac development><Cardiac infarction><Cardiovascular Diseases><ChIP assay><Cicatrix><Closure by Ligation><Coronary artery><Coupled><D-Glucose><Data><Death Rate><Development><Dextrose><Diabetes Mellitus><Diabetic mouse><Diagnostic><Dose><Echocardiogram><Echocardiography><Endothelium><Enzyme Gene><Enzymes><Epidemic><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Erythrocyte/Hepatoma Glucose Transporter><Fatty Acids><Fibroblasts><Fibrosis><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><GLUT><GLUT1><Gene Expression><Gene Modified><Genes><Genus Hippocampus><Glucose><Glucose Transporter 1><Glycolysis><Granulation Tissue><Heart><Heart Injuries><Heart artery><Heart failure><High Fat Diet><Histones><Hyperglycemia><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><Impairment><Infarction><Inflammation><Inflammatory><Inflammatory Response><Injections><Injury><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Intermediary Metabolism><Intervention><Intervention Strategies><Ischemia><KO mice><Ketone Bodies><Ketones><Ketosis-Resistant Diabetes Mellitus><Knock-out Mice><Knockout Mice><Left><Life Style><Lifestyle><Ligation><Macrophage><Maturity-Onset Diabetes Mellitus><Measures><Mediating><Mediator><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Mitochondria><Modification><Murine><Mus><Muscle Cells><Myocardial Infarct><Myocardial Infarction><Myocardial depression><Myocardial dysfunction><Myocytes><Mφ><NIDDM><Necrosis><Necrotic><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Null Mouse><O element><O2 element><Outcome><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Oxygen><Patients><Persons><Phase><Phenotype><Play><Preinterleukin 1 Beta><Preventative intervention><Production><Proliferating><Property><Proteins><Resolution><Risk><Risk Factors><Role><SLC2A1><SLC2A1 gene><STZ><Scars><Seahorse><Slow-Onset Diabetes Mellitus><Sodium Lactate><Solute Carrier Family 2, Facilitated Glucose Transporter, Member 1><Sorting><Source><Stable Diabetes Mellitus><Starvation><Streptozocin><Streptozotocin><T2 DM><T2D><T2DM><Techniques><Technology><Testing><Therapeutic><Therapeutic Intervention><Tissues><Transferase><Transferase Gene><Transthoracic Echocardiography><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><United States><Wound Repair><Zanosar><adult onset diabetes><adulthood><angiogenesis><anti-inflammatory effect><attenuate><attenuates><beta-Hydroxybutyrate><cardiac dysfunction><cardiac failure><cardiac function><cardiac infarct><cardiac injury><cardiogenesis><cardioprotectant><cardioprotection><cardioprotective><cardiovascular disorder><chromatin immunoprecipitation><clinical relevance><clinically relevant><co-morbid><co-morbidity><comorbidity><coronary attack><coronary infarct><coronary infarction><developmental><diabetes><diabetes mouse model><diabetic patient><driving><epigenetically><feeding><flow cytophotometry><four-dimensional imaging><function of the heart><gene modification><genetically modified><glucose metabolism><glucose uptake><healing><heart attack><heart development><heart dysfunction><heart formation><heart function><heart infarct><heart infarction><heart sonography><hyperglycemic><improved><in vivo><infarct><injuries><intervention for prevention><intervention therapy><interventional strategy><keto diet><ketogenic diet><ketosis resistant diabetes><maturity onset diabetes><metabolism measurement><metabolomics><metabonomics><mitochondrial><mortality><mortality rate><mortality ratio><mouse model><murine model><necrotic tissue><new approaches><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel approaches><novel drug target><novel druggable target><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><oxidation><pharmacologic><prevent><preventing><prevention intervention><preventional intervention strategy><preventive intervention><resolutions><social role><stable isotope><success><succinyl-CoA><succinyl-coenzyme A><therapeutic target><tissue necrosis><translational model><type 2 DM><type II DM><type two diabetes><ultrasound><wound healing><wound recovery><wound resolution><β-Hydroxybutyrate>