Ablation of cardiac TIGAR preserves myocardial energetics and cardiac function in the pressure overload heart failure model.

Authors:
Yoshifumi Okawa
Yoshifumi Okawa
Kyoto Prefectural University School of Medicine
Japan
Atsushi Hoshino
Atsushi Hoshino
National Institute for Basic Biology
Japan
Makoto Ariyoshi
Makoto Ariyoshi
Kyoto First Red Cross Hospital
Japan
Satoshi Kaimoto
Satoshi Kaimoto
Graduate School of Medical Science
Shuhei Tateishi
Shuhei Tateishi
Graduate School of Medical Science
Kazunori Ono
Kazunori Ono
Graduate School of Medical Science
Lucknow | India
Motoki Uchihashi
Motoki Uchihashi
Graduate School of Medical Science
Japan
Eri Iwai-Kanai
Eri Iwai-Kanai
Graduate School of Medicine
Japan

Am J Physiol Heart Circ Physiol 2019 Jun 22;316(6):H1366-H1377. Epub 2019 Mar 22.

Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine Kawaramachi-Hirokoji , Kyoto , Japan.

Despite the advances in medical therapy, the morbidity and mortality of heart failure (HF) remain unacceptably high. HF results from reduced metabolism-contraction coupling efficiency, so the modulation of cardiac metabolism may be an effective strategy for therapeutic interventions. Tumor suppressor p53 (TP53) and its downstream target TP53-induced glycolysis and apoptosis regulator (TIGAR) are known to modulate cardiac metabolism and cell fate. To investigate TIGAR's function in HF, we compared myocardial, metabolic, and functional outcomes between TIGAR knockout (TIGAR) mice and wild-type (TIGAR) mice subjected to chronic thoracic transverse aortic constriction (TAC), a pressure-overload HF model. In wild-type mice hearts, p53 and TIGAR increased markedly during HF development. Eight weeks after TAC surgery, the left ventricular (LV) dysfunction, fibrosis, oxidative damage, and myocyte apoptosis were significantly advanced in wild-type than in TIGAR mouse heart. Further, myocardial high-energy phosphates in wild-type hearts were significantly decreased compared with those of TIGAR mouse heart. Glucose oxidation and glycolysis rates were also reduced in isolated perfused wild-type hearts following TAC than those in TIGAR hearts, which suggest that the upregulation of TIGAR in HF causes impaired myocardial energetics and function. The effects of TIGAR knockout on LV function were also replicated in tamoxifen (TAM)-inducible cardiac-specific TIGAR knockout mice (/Tg(Myh6-cre/Esr1) mice). The ablation of TIGAR during pressure-overload HF preserves myocardial function and energetics. Thus, cardiac TIGAR-targeted therapy to increase glucose metabolism will be a novel strategy for HF. The present study is the first to demonstrate that TP53-induced glycolysis and apoptosis regulator (TIGAR) is upregulated in the myocardium during experimental heart failure (HF) in mice and that TIGAR knockout can preserve the heart function and myocardial energetics during HF. Reducing TIGAR to enhance myocardial glycolytic energy production is a promising therapeutic strategy for HF.

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Source
http://dx.doi.org/10.1152/ajpheart.00395.2018DOI Listing
June 2019

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(Supplied by CrossRef)
Article in Circulation
Hunt SA et al.
Circulation 2001

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