Wednesday, February 5, 2025
2/5/2025
Summary The Hippo signaling pathway is an evolutionarily conserved signaling pathway that controls organ size and tumorigenesis by regulating cell growth and death. We have shown that each component of the Hippo pathway is intimately involved in the pathogenesis of heart failure. YAP, the nuclear effector of the Hippo pathway, is transiently activated in response to pressure overload (PO) but downregulated during the chronic phase of PO and heart failure. Cardiac specific downregulation of YAP inhibits cardiac hypertrophy but promotes heart failure during the acute phase of PO, suggesting that endogenous YAP is salutary and mediates compensatory hypertrophy during the acute phase of PO. Although YAP is downregulated during the chronic phase of PO, forced activation of YAP at this stage is detrimental and promotes heart failure, due to de-differentiation of cardiomyocytes. Thus, YAP can be either protective or detrimental in a context-dependent manner during PO. However, it remains to be shown what makes YAP either salutary or detrimental during PO in the heart. Our preliminary results suggest that YAP promotes compensatory cardiac hypertrophy by stimulating glycolysis through upregulation of GLUT1 in the heart during the acute phase of PO, in a manner similar to aerobic glycolysis, namely the “Warburg effects” in cancer cells. Here we hypothesize that endogenous YAP mediates compensatory hypertrophy and survival of cardiomyocytes in the presence of PO through transcription of GLUT1 and consequent upregulation of glycolysis and biosynthetic molecules. YAP acts cooperatively with TEAD and HIF-1 and is involved in upregulation of GLUT1 that is activated during the acute phase of PO but inactivated during the chronic phase of PO due to differential availability of the partner transcription factors of YAP. To test these hypotheses, we will: 1. (a) Demonstrate that endogenous YAP plays an essential role in mediating upregulation of glycolysis in response to acute PO. (b) Demonstrate that activation of YAP induces accumulation of glycolytic intermediates through GLUT1- and PKM2-dependent mechanisms. (c) Demonstrate that YAP-induced upregulation of GLUT1 is essential for the maintenance of glycolysis and consequent upregulation of compensatory cardiac hypertrophy in response to acute PO. 2. Demonstrate that YAP-induced upregulation of GLUT1 is mediated through direct binding of YAP to TEAD and/or HIF-1 and resultant cooperative actions during acute PO. We will use genetically altered mouse models, cultured adult cardiomyocytes, metabolomic analyses, transcriptome analyses and ChIP sequencing analyses to address these issues. Successful completion of this project will provide novel information about the molecular switch that controls the glycolytic pathway and compensatory hypertrophy in the heart and how YAP differentially controls signaling mechanisms to mediate both salutary and detrimental effects in the heart during PO.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).