Abstract 9124: The Role of Mitochondrial Pyruvate Carrier on Myocardial Salvage Following Acute Myocardial Infarction

Abstract

Acute myocardial infarction (AMI) may progress to heart failure (HF). Ischemic-reperfusion injury (I/R) accounts for ~50% of the damage post-AMI. Currently, there are minimal interventions to mitigate I/R and prevent HF. Mitochondrial Pyruvate Carrier (MPC) is considered cardio-protective, and deletion causes HF. The purpose of this investigation was to determine if cardiac MPC deletion (MPC -/- ) in mice limits myocardial salvage following I/R. We hypothesized MPC -/- mice would have more necrosis and less myocardial salvage compared to wild type (WT) littermates.MPC1 was targeted in C57Bl/6 mice by placing loxP sites in the introns flanking the exon 3-5 of MPC1. A cardiac-specific deletion was used by intraperitoneal injections of tamoxifen at 8 weeks old. Four weeks post injection, prior to development of HF, mice were intubated, ventilated, and the left anterior descending artery was occluded for 30 minutes then reperfused for 2 hours. Next, Evans-Blue was injected into the heart to define the ischemic area. Hearts of paired littermates between WT (n=6) and MPC -/- (n=6) were excised and cut into 1-mm transverse slices. Slices were stained with triphenyltetrazolium-chloride (TTC) to define myocardial salvage. Next, slices were imaged and quantified by independent researchers using planimetry. Paired t-tests with an α-level of 0.05 were used to compare groups. Litters not subjected to I/R showed significant (p<0.001) MPC1 deletion (WT: 0.28±0.11 au vs. MPC -/- : 0.06±0.02 au). The area at risk (AAR) was comparable (p=0.12) between groups (WT: 46.7±5.9% vs. MPC -/- : 54.3±13.3), indicating equivalent coronary ligation-induced ischemia. Within the AAR, MPC -/- mice showed significantly (p=0.04) more necrosis (MPC -/- : 52.8±10.4% vs. WT: 42.7±17.4%) with less myocardial salvage (MPC -/- : 47.2±10.4% vs. WT: 57.3±10.6%). MPC -/- mice also had significantly (p=0.002) more absolute necrosis (28.4±7.8%) compared to WT mice (19.8±7.8%). There were no significant differences (p>0.05) in percent viable or salvageable tissue in relation to total area. In conclusion, following I/R, MPC -/- mice showed more absolute and standardized necrosis with less myocardial salvage, suggesting when cardiac MPC is reduced it causes more myocardial damage leading to HF.