Nuclear GAPDH Cascade Mediates Pathological Cardiac Hypertrophy

Pathological stressors disrupt cellular homeostasis, causing various diseases. We report a non-glycolytic role for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the pathological growth response of the heart. In cellular and animal models for cardiac hypertrophy, nuclear translocation of GAPDH was elicited in cardiac myocytes, followed by activation of p300 histone acetyl-transferase (HAT), an inducer of heart hypertrophy gene programs. The hypertrophy was inhibited by a compound antagonizing the nuclear GAPDH cascade. In mice with selective deletion of GAPDH’s nuclear function in cardiac myocytes, the stress-induced cardiac hypertrophy and functional deficits were normalized. Nuclear GAPDH cascade plays a pivotal role in stress response/homeostatic control in the heart. GAPDH may act as a key homeostatic mediator in living organisms through its stress-responsive nuclear translation. One-sentence summary Non-glycolytic function of GAPDH critically regulates heart homeostasis and mediates cardiac pathological hypertrophy