Inducible Overexpression of GLUT1 Prevents Mitochondrial Dysfunction and Attenuates Structural Remodeling in Pressure Overload but Does Not Prevent Left Ventricular Dysfunction

Abstract

BackgroundIncreased glucose transporter 1 (GLUT1) expression and glucose utilization that accompany pressure overload‐induced hypertrophy (POH) are believed to be cardioprotective. Moreover, it has been shown that lifelong transgenic overexpression of GLUT1 in the heart prevents cardiac dysfunction after aortic constriction. The relevance of this model to clinical practice is unclear because of the life‐long duration of increased glucose metabolism. Therefore, we sought to determine if a short‐term increase in GLUT1‐mediated myocardial glucose uptake would still confer cardioprotection if overexpression occurred at the onset of POH.Methods and ResultsMice with cardiomyocyte‐specific inducible overexpression of a hemagglutinin (HA)‐tagged GLUT1 transgene (G1HA) and their controls (Cont) were subjected to transverse aortic constriction (TAC) 2 days after transgene induction with doxycycline (DOX). Analysis was performed 4 weeks after TAC. Mitochondrial function, adenosine triphosphate (ATP) synthesis, and mRNA expression of oxidative phosphorylation (OXPHOS) genes were reduced in Cont mice, but were maintained in concert with increased glucose utilization in G1HA following TAC. Despite attenuated adverse remodeling in G1HA relative to control TAC mice, cardiac hypertrophy was exacerbated in these mice, and positive dP/dt (in vivo) and cardiac power (ex vivo) were equivalently decreased in Cont and G1HA TAC mice compared to shams, consistent with left ventricular dysfunction. O‐GlcNAcylation of Ca2+ cycling proteins was increased in G1HA TAC hearts.ConclusionsShort‐term cardiac specific induction of GLUT1 at the onset of POH preserves mitochondrial function and attenuates pathological remodeling, but exacerbates the hypertrophic phenotype and is insufficient to prevent POH‐induced cardiac contractile dysfunction, possibly due to impaired calcium cycling.

Enhanced Cardiac Akt/Protein Kinase B Signaling Contributes to Pathological Cardiac Hypertrophy in Part by Impairing Mitochondrial Function via Transcriptional Repression of Mitochondrion-Targeted Nuclear Genes

“…7 and 10). We previously reported that in pressure overload-induced heart failure, mitochondrial dysfunction develops and expression of mitochondrial regulatory genes and nucleus-encoded FAO and OXPHOS genes was repressed (2,37,38). Although the mechanism for repression of mitochondrial function in pressure overload-induced heart failure is likely multifactorial, we sought to explore the potential contribution of long-term Akt activation.…”

Glucose Transporters in Cardiac Metabolism and Hypertrophy

“…However, chronic increases in myocardial glucose uptake and utilization reduces the metabolic flexibility and renders the heart susceptible to contractile dysfunction in high fat diet induced obesity (259). Another study using an inducible overexpression model shows that short-term cardiac specific induction of GLUT1 at the onset of pressure overload preserves mitochondrial function and attenuates pathological remodeling, but exacerbates the hypertrophic phenotype and is insufficient to prevent pressure overload-induced cardiac contractile dysfunction (173). …”

“…These results suggest that promoting glucose utilization in the hypertrophied and failing heart could be beneficial. However, a short-term induction of GLUT1 in cardiomyocytes at the onset of pressure overload-induced hypertrophy failed to improve contractile function despite the beneficial effects on mitochondria function (173). Furthermore, the improvements in energetics and contractile function achieved by enhancing glucose uptake and utilization is not associated with any reduction of cardiac hypertrophy whereas preventing the shift of substrate preference to glucose decreases pathological hypertrophy during pressure overload (104, 125).…”

Structure of, and functional insight into the GLUT family of membrane transporters

“…[203][204][205] However, the actual cause of the heart failure in humans has not been directly determined. Some recent studies indicate that upregulated GLUT1 expression is related to HIV infection in T-cells.…”