Abstract 13936: Cardiac Beta3-Adrenergic Receptors Increase Pentose Phosphate Pathway Flux And Protect Against Hypertrophic Remodeling By Reducing Oxidative Stress

Abstract

Introduction: Cardiac beta3-adrenergic receptors (β3AR) mediate effects opposite to those of β1AR and β2AR and are upregulated during the development of hypertrophy or heart failure (HF). We previously showed that upon hemodynamic or neurohormonal stress β3AR confer protection against cardiac fibrosis and hypertrophic remodeling, two key components of the progression towards HF. Hypothesis: We tested the hypothesis that modulations of cardiac metabolism are implicated in the myocardial protection by β3AR Results: In a transgenic mouse model with cardiac-specific expression of the human β3AR (TG; compared to their wild-type littermates (WT)) myocardial glucose uptake is enhanced both in vivo ( 18 Fluoro-deoxy-glucose by PET-CT) and in isolated adult cardiac myocytes exposed to hemodynamic stress by transverse aortic constriction for 9 weeks (TAC). In addition, a decrease in glycaemia during insulin tolerance test as well as an increase in Glut4 transporter in TG post-TAC suggest an insulin-dependency, as well as sensitization underlying the accrued glucose entry. Targeted metabolomics on cardiac tissue from TG (vs. WT) revealed a significant increase of several intermediates of the pentose phosphate pathway (PPP) post-TAC. Transcriptional expression from isolated cardiac myocytes showed an upregulation of several key enzymes of the pathway, that correlate with an elevation of NADPH levels, a major product of the PPP, with no modifications in nucleotides levels, implying a re-entry via the lower glycolysis. Consistent with an upregulated PPP, we found an increase in the ratio of reduced-to-oxidized Glutathione and a decrease in several indicators of oxidative stress (ROS production, MetO) both indicating a reduced oxidative stress. Conclusion: β3AR mediate an increased flux through the PPP, sustained by an enhanced glucose uptake, in cardiac myocytes upon prolonged hemodynamic stress. The associated renewal of the NADPH pool and cellular detoxification of ROS may contribute to the protective role of β3AR against hypertrophic remodeling. As β3AR agonists are currently used in clinical practice for urological indications, these original cardiac protective mechanisms may offer immediate perspectives for the prevention or treatment of HF.