ATP‐dependent Crosstalk Between C‐Jun N‐terminal Kinase (JNK) and ERK/Akt Determines Survival of Cardiac Myocytes Subjected to Hypoxia‐Reoxygenation

The role of JNK in myocardial ischemic‐reperfusion injury is unknown because both protective and injurious properties have been reported. HYPOTHESIS JNK switches from a positive to negative survival role during reoxygenation as glucose and ATP are depleted by hypoxia. METHODS Isolated cardiac myocytes (CM) were cultured under hypoxia with normal (5mM (NG)) or low (0.5mM (LG)) glucose and reoxygenated after 8h. Signaling intermediates, death markers and cell survival were quantified. RESULTS During hypoxia glucose was depleted within 4h and ATP declined to 18±7% at 8h in the LG condition whereas CM subjected to hypoxia with NG displayed only minor loss of these energy intermediates. CM death after reoxygenation was significantly greater in LG but pharmacological or genetic JNK inhibition was protective. Conversely lower CM death in NG was markedly increased by inhibition of JNK. Other death pathway markers including cytochrome c release, mitochondrial permeability transition pore (mPTP) and caspase 3 activity responded in parallel and confirmed the energy‐dependent switch in the role of JNK. We found that JNK supported increased p‐Akt and p‐Erk1/2 activity selectively in the NG condition and this was significantly responsible for the functional switch. CONCLUSIONS JNK protects myocytes in an energy‐dependent manner by differential regulation of Akt and Erk. Funded by NIH RO1# HL092499 .