Nuclear GAPDH signaling mediates pathological cardiac hypertrophy

Pathological stressors disrupt cellular and organ homeostasis, causing various diseases. We discovered a novel role for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the pathological growth response of the heart, independent of its functions in glycolysis and cell death. In a cellular model for cardiac hypertrophy, endothelin-1 elicited nuclear translocation of GAPDH and activation of p300 histone acetyl-transferase (HAT), followed by activation of myocyte enhancer factor 2 (MEF2). GAPDH nuclear translocation and p300 HAT activation was also identified in rodent pathological hypertrophied hearts. The hypertrophy was markedly ameliorated by molecular and pharmacological interventions that antagonize the nuclear GAPDH pathway, including a novel antagonist selective to its nuclear function. This pathway may be the key to stress response/homeostatic control, and thus the potential therapeutic target for stress-associated diseases.One-sentence summaryThis study shows a novel function of GAPDH in homeostatic control of the heart, which is disturbed and results in cardiac hypertrophy with pathological stressors.