Ventricular tissues obtained during LVAD implantation in humans with advanced heart failure (HF) demonstrate a global reduction in fuel metabolism. Hearts that increase systolic function with mechanical unloading (responders) are associated with enhanced mitochondrial function and a significant increase in glycolysis, without a coordinate increase in pyruvate utilization or mitochondrial TCA cycle flux (Project 1). In this Project, we hypothesize that (1) a mismatch in glycolysis and pyruvate metabolism may impair functional recovery, (2) this mismatch is related to reduced expression of the mitochondrial pyruvate carrier (MPC), and (3) strategies that coordinately increase glucose uptake and oxidation will promote LV recovery. Although glycolytic induction might activate cardioprotective mechanisms, these can be offset by impairment in mitochondrial pyruvate utilization. This latter effect may involve excessive activation of HIF-1 alpha, resulting, in part, from accumulation of 2-hydroxyglutarate (2-HG). Therefore, we have generated novel murine models with inducible overexpression of the GLUT1 glucose transporter and mice with inducible deletion or overexpression of MPC1 that will be subjected to a reproducible in vivo model of HF regression, achieved by reversal of transverse aortic constriction (TAC) termed de-banding. Aim 1 will test the hypothesis that increasing glycolysis by inducing GLUT1 protein post-TAC will accelerate LV recovery with pressure-relief. Aim2 will test the hypothesis that reducing MPC1 expression will exacerbate pressure-overload-induced LV remodeling and limit reverse re-modeling post-TAC. Aim 3 will test the hypothesis that cardioprotection afforded by increased glycolysis following pressure overload will be abrogated by MPC1 deficiency, but will be augmented when MPC1 expression is restored or maintained. Aim 4 will test the hypothesis that accumulation of 2-hydroxyglutarate (2-HG) reflects a metabolomics signature that will correlate with the degree of glycolysis/pyruvate oxidation mismatch in animal models and could represent a prognostic biomarker for functional and metabolic cardiac recovery in human HF. Successful completion of these studies will provide a strong mechanistic underpinning for determining if the relationship between glycolysis and pyruvate oxidation is predictive of functional recovery (Project 1) and if circulating 2-HG could represent a robust biomarker that will inform prognosis and outcome (Project 3).
|Program type||Strategically Focused Research Network|
|Effective start/end date||07/01/2016 → 06/30/2020|