Project Grant F30HL180006

ELUCIDATING THE NON-METABOLIC ROLE OF KETONE BODIES IN HEART FAILURE - ABSTRACT HEART FAILURE IS ONE OF THE MAIN CAUSES OF MORTALITY WORLDWIDE. RECENTLY, THERE HAS BEEN INCREASING INTEREST IN THE ROLE THAT DIETARY INTAKE HAS ON METABOLIC DYSFUNCTION IN HEART FAILURE AND POTENTIAL NUTRITIONAL OR PHARMACOLOGICAL INTERVENTIONS THAT MAY IMPROVE THIS CONDITION. MANY STUDIES HAVE DEMONSTRATED A PARTICULARLY BENEFICIAL ROLE OF THE KETOGENIC DIET IN HEART FAILURE, WHICH WAS THOUGHT TO BE DUE TO THE ABILITY OF THE HEART TO UTILIZE KETONE BODIES AS A FUEL SOURCE TO SUPPLEMENT DECREASED FATTY ACID OXIDATION AND ANAEROBIC GLYCOLYSIS IN THE SETTING OF HEART FAILURE. WE RECENTLY DEVELOPED A MURINE HEART FAILURE MODEL WHICH MIMICKED THIS SHIFT TOWARDS ANAEROBIC GLYCOLYSIS WITH CARDIAC-SPECIFIC MITOCHONDRIAL PYRUVATE CARRIER DELETION. WHILE A HIGH-FAT, LOW- CARBOHYDRATE KETOGENIC DIET WAS ABLE TO PREVENT AND REVERSE HEART FAILURE IN THIS MODEL, WE OBSERVED A PARADOXICAL DOWNREGULATION OF KETONE BODY METABOLISM. THIS IS ALSO OBSERVED IN PRESSURE OVERLOAD MODELS OF HEART FAILURE. KETONE BODIES HAVE RECENTLY BEEN DISCOVERED TO HAVE SEVERAL REGULATORY MECHANISMS OUTSIDE OF THEIR TRADITIONAL ROLE AS A METABOLIC FUEL, INCLUDING POSTTRANSLATIONAL MODIFICATION OF ENZYMES AND HISTONES INVOLVED IN SEVERAL IMPORTANT CELLULAR PATHWAYS. WE HAVE ALSO OBSERVED THIS FINDING IN OUR OWN EXPERIMENTS, AND WHEN COUPLED WITH OUR FINDINGS THAT KETONE BODY METABOLISM WAS DOWNREGULATED IN HEARTS RESCUED BY A KETOGENIC DIET, THIS SUGGESTS A POTENTIALLY IMPORTANT NON-METABOLIC ROLE OF KETONE BODIES IN HEART FAILURE THAT HAS GONE PREVIOUSLY UNEXPLORED. IN THESE STUDIES, WE WILL SEPARATE THE METABOLIC VERSUS REGULATORY ROLES OF KETONE BODIES IN IMPROVING HEART FAILURE USING A GENETIC KNOCKOUT MOUSE MODEL THAT INHIBITS KETONE BODY METABOLISM TO ISOLATE THE NON-METABOLIC EFFECTS OF KETONE BODIES. WE WILL DEVELOP HEART FAILURE IN MICE USING BOTH A PRESSURE OVERLOAD AND THE MITOCHONDRIAL PYRUVATE CARRIER KNOCKOUT MODEL, AND WE WILL EXAMINE THE ABILITY OF THE KETOGENIC DIET TO RESCUE HEART FAILURE IN EACH OF THESE MICE WHEN KETONE BODY METABOLISM IS INHIBITED. SINCE KETONES HAVE BEEN OBSERVED TO HAVE ANTIOXIDANT EFFECTS, AND WE DETECTED MODIFICATION OF THE MITOCHONDRIAL MANGANESE SUPEROXIDE DISMUTASE (SOD2), WE WILL ASSESS OXIDATIVE STRESS RESPONSE IN EACH OF THESE TREATMENTS AND PERFORM IN VITRO EXPERIMENTS TO ASSESS THE SIGNIFICANCE OF KETONE BODY POST-TRANSLATIONAL MODIFICATIONS. THE FINDINGS OF THIS STUDY WILL UNVEIL NOVEL REGULATORY MECHANISMS OF HEART FAILURE AND WILL HIGHLIGHT VITAL TARGETS OF FURTHER PHARMACOLOGICAL OR NUTRITIONAL INTERVENTIONS TO IMPROVE HEART FAILURE PROGRESSION AND OUTCOMES. THIS PROJECT WILL BE CONDUCTED AT SAINT LOUIS UNIVERSITY SCHOOL OF MEDICINE IN THE BIOCHEMISTRY AND MOLECULAR BIOLOGY DEPARTMENT. THE FOCUS OF THE FELLOWSHIP TRAINING PLAN IS ON RESEARCH, WITH TECHNICAL TRAINING, WEEKLY SEMINARS AND JOURNAL CLUBS, PRESENTATION AT SYMPOSIA, AND MAINTAINED CLINICAL EXPERIENCES PROVIDED FOR CAREER DEVELOPMENT.