Abstract 16727: A First Description of Increased Glutaminolysis in Experimental Right Ventricular Hypertrophy; Association With Ischemia-Induced Activation of cMyc
INTRODUCTION We have previously showed that in right ventricular hypertrophy (RVH) and RV failure there is a maladaptive metabolic switch from glucose oxidation to glycolysis. A similar metabolic shift occurs in many cancers. Another metabolic derangement in cancer that is a metabolic shift to use glutamine as a substrate, glutaminolysis, has not been studied in RVH. cMyc, an oncogenic transcription factor, cooperating with hypoxia-induced factor 1, induces both glycolysis and glutaminolysis in cancer cells. We hypothesized that cMyc activation induces glutaminolysis in RVH.
METHODS AND RESULTS 3 groups of Sprague-Dawley rats were studied: 1) Control; 2) Pulmonary artery banding (PAB), in which RVH is induced by a 1.3mm pulmonary artery band; 3) Monocrotaline-induced RVH, elicited by subcutaneous injection of monocrotaline (60mg/Kg). RVH occurred with PAB and monocrotaline, evident from increased RV/LV+septum (P<0.001 vs control). In an RV Langendorff model, total coronary flow collected from coronary sinus was reduced in PAB and monocrotaline models vs control (P<0.01). Staining for CD31 and lectin (both markers of endothelial cells) demonstrated that capillary density was reduced in both RVH models vs control (P<0.05). The RV in monocrotaline model had lower capillary densities than RV in PAB model (P<0.05). cMyc expression was significantly increased in RV in both RVH models (P<0.05 vs control). cMyc also was increased in LV in monocrotaline model (P<0.05 vs control) but was unchanged in LV in PAB model. mRNA expression of the glutamine transporters, SLC7A5 and SLC1A5, were increased in both RV and LV in monocrotaline RVH (P<0.05 vs control); whereas only SLC7A5 expression was elevated in PAB RVs (P<0.05 vs control).
CONCLUSION There is an increase of glutaminolysis in RV in RVH models. This is associated with RV ischemia and capillary rarefaction. It is unclear whether the observed cMyc activation is caused by or induces the capillary rarefaction. However, it is likely cMyc accounts for the increased glutaminolysis which is a newly recognized metabolic abnormality in RVH models. Our study suggests the potential of therapeutic inhibition of glutaminolysis as a treatment for RVH and RV failure.
- © 2011 by American Heart Association, Inc.