Presentation description

Worldwide 3 million people experience an acute myocardial infarction (AMI), increasing their risk of developing heart failure. Primary percutaneous coronary intervention is a necessary clinical therapy, which restores blood flow to the ischemic heart. However, this rapid reintroduction leads to further myocardial damage, known as ischemic-reperfusion injury (I/R), accounting for half of the total myocardial damage. Currently, no pharmacological therapies exist to minimize I/R. Previous research suggests the mitochondrial pyruvate carrier (MPC1) is cardioprotective, and inhibition of the molecule monocarboxylate transporter 4 (MCT4) increases myocardial salvage. This study investigated the relationship between MPC1 and MCT4 inhibition on myocardial salvage by assessing mitochondrial respiration. By using the highly selective small-molecule VB124 to inhibit MCT4, we hypothesize myocardial salvage after I/R will increase, and propose it as an effective pharmacological therapy. We also hypothesize this mechanism is dependent on pyruvate oxidation via MPC1. This study used cardiac-specific, tamoxifen inducible MPC1CKO mice in vivo and in vitro I/R models. In our in vivo model an AMI was induced and reperfusion was allowed for 2 hrs, the heart was then excised. In our in vitro model adult cardiomyocytes were exposed to normoxia, hypoxia+reoxygenation with VEH, and hypoxia+reoxygenation with VB124. Images of the heart were captured to assess myocardial damage post-injury. Mitochondrial respiration levels were measured using a Seahorse stress test assay. Following I/R, myocardial salvage is significantly reduced (p=0.04) in MPC1CKO (47.21±4.22%, n=6) when compared to WT (57.28±7.09%, n=6). Additionally, mitochondrial respiration rates were lower in MPC1CKO while WT mitochondrial respiration rates were moderately higher in hypoxia+reoxygenation with VB124 compared to hypoxia+reoxygenation VEH and normoxia. After I/R VB124 does not rescue MPC1CKO mitochondrial respiration but does enhance WT respiration, highlighting it as a potential pharmacological therapy for I/R.