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Huamei He, PhD, MD
Pronouns
He/Him/His
Job Title
Lecturer
Academic Rank
Department
Medicine
Authors
Huamei He, Ryan M. Mulhern, William M. Oldham, Wusheng Xiao, Yi-Dong Lin, Ronglih Liao, Joseph Loscalzo
Principal Investigator
Joseph Loscalzo
Research Category: Cardiovascular, Diabetes, and Metabolic Disorders
Tags
L-2-hydroxyglutarate (L2HG) couples mitochondrial and cytoplasmic energy metabolism to support cellular redox homeostasis. Under oxygen-limiting conditions, mammalian cells generate L2HG to counteract the adverse effects of reductive stress induced by hypoxia. We examined the cardioprotective effects of L2HG accumulation against ischemic injury and its underlying mechanism using genetic mouse models. L2HG accumulation was induced by homozygous or heterozygous deletion of the L2HG dehydrogenase (L2HGDH) gene in mice. Four acute myocardial ischemia models (90-min ex vivo low-flow ischemia, 30-min ex vivo no-flow ischemia followed by 60- or 120-min reperfusion, and 30-min in vivo regional myocardial ischemia followed by 24-hours reperfusion) were established. Using [13C]- and [31P]-NMR spectroscopy, high performance liquid chromatography, real-time qRT-PCR, ELISA, triphenyltetrazolium staining, and echocardiography, we found that L2HGDH deletion induces L2HG accumulation at baseline and under stress conditions with significant functional consequences. In response to both low-flow ischemia and no-flow ischemia-reperfusion, L2HG accumulation shifts glucose flux from glycolysis towards the pentose phosphate pathway (PPP). These key metabolic changes were accompanied by enhanced cellular reducing potential, increased elimination of reactive oxygen species, attenuated oxidative injury and myocardial infarction, preserved cellular energy state, and improved cardiac function in L2HGDH-deleted hearts compared with control hearts under ischemic stress conditions. Our study demonstrates that L2HGDH deletion-induced L2HG accumulation protects against myocardial injury under low-flow ischemia and no-flow ischemia followed by reperfusion through a metabolic shift of glucose flux from glycolysis towards the PPP.
We previously found that L-2-hydroxyglutarate (L2HG) increases in cardiovascular cells in response to hypoxia. This metabolite is derived from α- ketoglutarate, a key intermediate in the tricarboxylic acid cycle. Once formed, L2HG has no other metabolic fate except to undergo oxidation back to α- ketoglutarate by the stereospecific L2HG dehydrogenase (L2HGDH). The role of L2HG in human metabolism is unknown. We hypothesized that it suppresses glycolysis and/or increases pentose phosphate pathway activity under hypoxia. To address our hypothesis, we established four acute myocardial ischemia models (90-min ex vivo low-flow ischemia, 30-min ex vivo no-flow ischemia followed by 60- or 120-min reperfusion, and 30-min in vivo regional myocardial ischemia followed by 24-hours reperfusion) in genetic murine models with L2HGDH gene deletion. Using multidisciplinary techniques, including nuclear magnetic resonance spectroscopy, high performance liquid chromatography, enzyme-linked immunosorbent assay, triphenyltetrazolium chloride staining, colorimetric/fluorometric spectroscopy, and echocardiography, we demonstrated that L2HGDH gene deficiency causes L2HG accumulation, which protects against myocardial injury in the setting of low-flow ischemia or ischemia/reperfusion injury, and does so by shifting glucose flux toward the pentose phosphate pathway to eliminate reactive oxygen species from myocardial tissue, mitigate redox stress, reduce myocardial infarct size, preserve high energy phosphates and improve cardiac function. Our findings provide a potential new therapeutic strategy for cardiovascular diseases induced by low-flow ischemia and ischemia-reperfusion.
