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.
Highlights
Cardiac hypertrophy is an initial response of the heart to hemodynamic overload, including high blood pressure, termed pressure overload (PO)
Endogenous Yes-associated protein 1 (YAP) plays an essential role in mediating glucose transporter 1 (GLUT1) upregulation and glycolysis in response to PO We have shown previously (3) that YAP is activated in response to acute PO, and that cardiac specific heterozygous downregulation of YAP (YAPchKO) normalizes the level of nuclear YAP, inhibits hypertrophy despite the presence of cardiac dilation, and promotes heart failure during acute PO
Since activation of glycolysis is intimately involved in cell growth, including cardiac hypertrophy (12, 14), we first tested whether YAP is involved in activation of glycolysis during acute PO in the heart
Summary
Cardiac hypertrophy is an initial response of the heart to hemodynamic overload, including high blood pressure, termed pressure overload (PO). Long-term cardiac PO often elicits other pathological effects in cardiac muscle, including cell death, inflammation, and fibrosis, thereby causing contractile dysfunction (1). Cardiac hypertrophy alone is not always pathological; increasing wall thickness produces more contractile force and reduces wall stress and oxygen consumption. Hypertrophy can remain adaptive without progressing into failure (1). Activation of signaling mechanisms stimulating adaptive hypertrophy can alleviate pathological hypertrophy (1, 2). Failure to activate adaptive mechanisms during hemodynamic overload is devastating (3, 4). It is clinically important to elucidate the signaling mechanism mediating the adaptive form of cardiac hypertrophy
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