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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Research Article Cardiology

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 13

YAP physically interacts with both TEAD1 and HIF-1α.

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YAP physically interacts with both TEAD1 and HIF-1α. (A–C and G) HEK293 ...
(A–C and G) HEK293 cells were transfected with plasmids encoding FLAG-YAP, Myc-TEAD1, and HA–HIF-1α P402A/P564A, a stable HIF-1α mutant. (D–F) NRVMs were transduced with Ad-FLAG-YAP, Ad-Myc-TEAD1, and Ad-HA–HIF-1α P402A/P564A. The cells were treated with 3 μM MG-132 twenty-four hours prior to being harvested. Immunoblotting (IB) and immunoprecipitation (IP) were performed using the indicated antibodies. Data are representative of 3 independent blots. The lanes were run on the same gel but were noncontiguous (A–G). (H–K) YAP directly bound to both TEAD1 and HIF-1α, while TEAD1 and HIF-1α only interacted with one another through YAP. The indicated GST-fused proteins and recombinant proteins were incubated, followed by pulldown with glutathione-sepharose beads. Data are representative of 3 independent blots. (L) Schematic illustration of the role of YAP in regulating CM glycolysis in the heart during acute PO.