Presenting Author:

Katherine Fallon

Principal Investigator:

Elizabeth McNally, M.D.

Department:

Medicine

Keywords:

Glucose metabolism, sulfonylurea receptor, sulfonylureas, metabolism, mouse model, cardiac glycolysis, GLUT4, SUR2, meta... [Read full text] Glucose metabolism, sulfonylurea receptor, sulfonylureas, metabolism, mouse model, cardiac glycolysis, GLUT4, SUR2, metabolic transition, substrate utilization, vasospasm, arrhythmia [Shorten text]

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B28 - Basic Science

SUR2 regulates cardiac glycolytic metabolism through interactions with Glut4

Changes in cardiac metabolism are required for cardiac maturation, adaptation to available substrates, and during pathological events. Sulfonylurea receptor 2 (SUR2) is an ABC transporter protein containing a nucleotide-binding fold that senses the intracellular ADP/ATP ratio. SUR2 partners with the potassium channel Kir6.2, linking metabolic state with membrane potential. SUR2 is encoded by the Abcc9 gene. Mice with global deletion of Abcc9/SUR2 die by 3 weeks of age due to a failure to transition from glycolytic to oxidative substrate utilization. We hypothesize that SUR2 regulates glucose metabolism through its interactions with other proteins. To study the absence of SUR2 in adult mouse hearts, we generated a mouse model with tamoxifen inducible deletion of Abcc9/SUR2 in the adult heart. We established that this deletion strategy reduces Abcc9/SUR2 effectively in cardiomyocytes and does not result in lethality in adult mice. Cardiac function and gross morphology are not altered following cardiac-specific reduction of SUR2 under normal conditions. Electron microscopy of the ventricular myocardium reveals sarcomere derangement and a decrease in mitochondrial size. Isolated cardiomyocyte and mitochondria show approximately a 30% increase in oxygen consumption rate in the absence of SUR2. Using in-silico analysis of gene expression patterns we identified that SUR2 and GLUT4 are highly co-regulated. Cardiomyocytes lacking SUR2 show significantly higher insulin-dependent glucose uptake than controls. Evaluation of GLUT4 localization in response to insulin shows reduced translocation to the sarcolemma in membrane and to the microsomal membraneous fractions from hearts lacking SUR2. Both immunofluorescence microscopy and co-immunoprecipitation identified an interaction between SUR2 and GLUT4. AKT signaling is required to facilitate the translocation of GLUT4 to the sarcolemma following insulin stimulation. After insulin treatment, mice with cardiomyocyte-specific SUR2 deletion show aberrantly phosphorylated AKT levels, indicating SUR2 plays a yet undetermined role in these signaling events. These data suggest a mechanism by which loss of SUR2 alters the cardiac metabolic state. In states lacking SUR2, we hypothesize that GLUT4 is not properly internalized following insulin signaling, leading to excess glucose uptake.