MEKK1 suppresses oxidative stress-induced apoptosis of embryonic stem cell-derived cardiac myocytes

A combination of in vitro embryonic stem (ES) cell differentiation and targ eted gene disruption has defined complex regulatory events underlying oxida tive stress-induced cardiac apoptosis, a model of postischemic reperfusion injury of myocardium. ES cell-derived cardiac myocytes (ESCM) having target ed disruption of the MEKK1 gene were extremely sensitive, relative to wild- type ESCM, to hydrogen peroxide-induced apoptosis. In response to oxidative stress, MEKK1-/- ESCM failed to activate c-Jun kinase (JNK) but did activa te p38 kinase similar to that observed in wild-type ESCM, The increased apo ptosis was mediated through enhanced tumor necrosis factor cu production, a response that was positively and negatively regulated by p38 and the MEKK1 -JNK pathway, respectively. Thus, MEKK1 functions in the survival of cardia c myocytes by inhibiting the production of a proapoptotic cytokine. MEKK1 r egulation of the JNK pathway is a critical response for the protection agai nst oxidative stress-induced apoptosis in cardiac myocytes.