Abstract 17367: Tigar (tp53-induced Glycolysis And Apoptosis Regulator) Decreases Glycogenic Energy Metabolism and Deteriorates Left Ventricular Function in Pressure Overload-induced Heart Failure Model
Background: In spite of the metabolic alterations in heart failure (HF), only recently have the mechanisms underlying these changes been identified. Tumor suppressor p53 responds to metabolic changes thorough several mechanisms. One of the p53 targets, TIGAR (TP53-induced glycolysis and apoptosis regulator) reduces glycolysis and suppresses autophagy, which augments ischemic damage, however its role on HF is unclear.
Method and Results: To investigate the role of TIGAR, we performed thoracic transverse aortic constriction (TAC)-operation. After four weeks of TAC, left ventricular (LV) function in wild type mice was decreased with TIGAR induction, which was not seen in TIGAR knockout mice. Next, we used TIGAR conditional knockout mouse (TIGARflox/flox) and a tamoxifen-inducible cardiac-specific Cre transgene (MerCreMer+). Four weeks after TAC, LV contraction was preserved in tamoxifen pretreated TIGARflox/flox;MerCreMer+ littermates with low grade fibrosis between littermates. TIGARflox/flox;MerCreMer+ littermates exhibited up-regulation of glucose utilization, high energy phosphate(HEP), and autophagic flux. Inhibiting autophagy with chloroquine did not reverse the protective effect of TIGAR deletion. To evaluate on late phase HF, we treated littermates with tamoxifen 2 weeks after TAC, followed by analysis at 8 weeks. LV dysfunction was also reduced in tamoxifen mid-treated TIGARflox/flox;MerCreMer+ littermates.
Conclusions: TIGAR attenuates adaptive response such as up-regulation of glycolysis in HF. Inhibition of TIGAR improved HEP and protected from HF even after the onset of heart failure.
- © 2013 by American Heart Association, Inc.