Abstract 16722: L-2-Hydroxyglutarate Protects Against Myocardial Ischemia-Reperfusion Injury

Abstract

Background: L-2-hydroxyglutarate (L2HG) couples mitochondrial (Mito) and cytoplasmic energy metabolism in a model of cellular redox regulation. Under conditions of limited oxygen availability, mammalian cells generate L2HG to counteract the adverse effects of Mito reductive stress induced by hypoxia. L2HG is oxidized to α-ketoglutarate by L2HG dehydrogenase (L2HGDH) in a variety of mammalian tissues, including the heart. Myocardial ischemia/reperfusion injury (MIRI) is a consequence of coronary vascular disease and vascular procedures. Mito oxidative stress plays a critical role in MIRI. Here we hypothesized that L2HG protects against MIRI. Methods and Results: We induced accumulation of L2HG by heterozygous (HET) and homozygous (KO) deletion of L2HGDH gene in mice. The hearts isolated from HET, KO, and wild-type (WT) littermate mice were subjected to 30 min global thermal ischemia followed by 60 min reperfusion. Cardiac function and energy metabolism were simultaneously measured using a Langendorff heart perfusion model and 31 P-NMR spectroscopy. We found that female HET and KO exhibited better recovery of cardiac function post-MIRI in consistent with better preservation of intracellular ATP and phosphocreatine (Table). Using HPLC, we measured compounds representative of cellular redox state (GSG, GSSG, NAD, NADH, NADP, NADPH, coenzyme A and ascorbate), cellular energy state (ATP, ADP, AMP, GTP, GDP, GMP, UTP, UDP, UMP, CTP, CDP, CMP, IMP, malonyl-CoA and acetyl-CoA), and nucleotide catabolism (adenosine, hypoxanthine, xanthine and inosine) in freeze-clamped hearts. We found that ratios of GSH/GSSG and ATP/ADP increased in HET and KO hearts (Table). Interestingly, the ratios of NADH/NAD and NADPH/NADP increased only in KO but not in HET hearts. Consistent with the increased ratio of ATP/AMP, hypoxanthine and xanthine decreased only in KO hearts but not in HET hearts (Table). Conclusion: The accumulation of L2HG in a genetic mouse model protects against MIRI though increasing cellular antioxidative capacity and preserving high energy phosphates. The underlying mechanism of these beneficial adaptive phenomena warrants further study. Targeting L2HG levels and L2HGDH expression may serve as new therapeutic strategies for MIRI protection.