YAP mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overload
Toshihide Kashihara, … , Maha Abdellatif, Junichi Sadoshima
Toshihide Kashihara, … , Maha Abdellatif, Junichi Sadoshima
Published February 8, 2022
Citation Information: J Clin Invest. 2022;132(6):e150595. https://doi.org/10.1172/JCI150595.
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YAP mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overload

Abstract

The heart utilizes multiple adaptive mechanisms to maintain pump function. Compensatory cardiac hypertrophy reduces wall stress and oxygen consumption, thereby protecting the heart against acute blood pressure elevation. The nuclear effector of the Hippo pathway, Yes-associated protein 1 (YAP), is activated and mediates compensatory cardiac hypertrophy in response to acute pressure overload (PO). In this study, YAP promoted glycolysis by upregulating glucose transporter 1 (GLUT1), which in turn caused accumulation of intermediates and metabolites of the glycolytic, auxiliary, and anaplerotic pathways during acute PO. Cardiac hypertrophy was inhibited and heart failure was exacerbated in mice with YAP haploinsufficiency in the presence of acute PO. However, normalization of GLUT1 rescued the detrimental phenotype. PO induced the accumulation of glycolytic metabolites, including l-serine, l-aspartate, and malate, in a YAP-dependent manner, thereby promoting cardiac hypertrophy. YAP upregulated the GLUT1 gene through interaction with TEA domain family member 1 (TEAD1) and HIF-1α in cardiomyocytes. Thus, YAP induces compensatory cardiac hypertrophy through activation of the Warburg effect.

Authors

Toshihide Kashihara, Risa Mukai, Shin-ichi Oka, Peiyong Zhai, Yasuki Nakada, Zhi Yang, Wataru Mizushima, Tsutomu Nakahara, Junco S. Warren, Maha Abdellatif, Junichi Sadoshima

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Figure 12

YAP, TEAD1, and HIF-1α bind to the Glut1 promoter in the heart.

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YAP, TEAD1, and HIF-1α bind to the Glut1 promoter in the heart. (A) Sche...
(A) Schematic representation of HREs and the predicted TRE in the mouse Glut1 promoter. The predicted TRE differs in 2 base pairs (green) from the consensus TRE. Point mutations are indicated in red. (B and C) Effects of siRNA against Tead1 or Hif1a (B) and Glut1 promoter mutations (C) on YAP-induced activation of the Glut1 promoter. n = 6–10 wells from 3–4 independent experiments. *P < 0.05 versus each mock; #P < 0.05 versus each control YAP; and †P < 0.05 versus control mock, by 1-way ANOVA with Tukey’s test. (D and E) ChIP assays of the Glut1 promoter were performed in NRVMs using the indicated antibodies. n = 4 dishes from 2 independent experiments. *P < 0.05, by 1-way ANOVA with Tukey’s test. (F–H) ChIP assays of the Glut1 promoter were performed using pooled hearts from WT mice after 2 days of sham operation or TAC, with antibodies against YAP (F), TEAD1 (G), and HIF-1α (H). (I–L) ChIP assays of the Glut1 promoter were performed using hearts from control or YAPch-KO mice after 2 days of sham operation or TAC, with antibodies against HIF-1α (I and J) and TEAD1 (K and L). n = 4–6 mice. *P < 0.05, by 1-way ANOVA with Tukey’s test. (M) ChIP-Seq was performed using pooled hearts from WT mice subjected to sham operation or 4 days of TAC with anti-YAP antibody. Schematic representation of the Glut1 promoter is aligned with the results of ChIP-Seq in the Glut1 promoter. Triangles indicate new peaks after PO. ATG, start codon. Data represent the mean ± SEM.