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Knockout of TIGAR enhances myocardial phosphofructokinase activity and preserves diastolic function in heart failure

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Hypertension is an important risk factor in the pathogenesis of diastolic dysfunction. Growing evidence indicates that glucose metabolism plays an essential role in diastolic dysfunction. TP53‐induced glycolysis and apoptosis regulator… Click to show full abstract

Hypertension is an important risk factor in the pathogenesis of diastolic dysfunction. Growing evidence indicates that glucose metabolism plays an essential role in diastolic dysfunction. TP53‐induced glycolysis and apoptosis regulator (TIGAR) has been shown to regulate glucose metabolism and heart failure (HF). In the present study, we investigated the role of TIGAR in diastolic function and cardiac fibrosis during pressure overload (PO)‐induced HF. WT mice subjected to transverse aortic constriction (TAC), a commonly used method to induce diastolic dysfunction, exhibited diastolic dysfunction as evidenced by increased E/A ratio and E/E′ ratio when compared to its sham controls. This was accompanied by increased cardiac interstitial fibrosis. In contrast, the knockout of TIGAR attenuated PO‐induced diastolic dysfunction and interstitial fibrosis. Mechanistically, the levels of glucose transporter Glut‐1, Glut‐4, and key glycolytic enzyme phosphofructokinase 1 (PFK‐1) were significantly elevated in TIGAR KO subjected to TAC as compared to that of WT mice. Knockout of TIGAR significantly increased fructose 2,6‐bisphosphate levels and phosphofructokinase activity in mouse hearts. In addition, PO resulted in a significant increase in perivascular fibrosis and endothelial activation in the WT mice, but not in the TIGAR KO mice. Our present study suggests a necessary role of TIGAR‐mediated glucose metabolism in PO‐induced cardiac fibrosis and diastolic dysfunction.

Keywords: tigar; heart failure; knockout tigar; diastolic dysfunction; fibrosis

Journal Title: Journal of Cellular Physiology
Year Published: 2022

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