Genetic inhibition or activation of JNK1/2 protects the myocardium from ischemia-reperfusion-induced cell death in vivo.

摘要: The c-Jun NH2-terminal kinase (JNK) branch of the mitogen-activated protein signaling cascade has been implicated in regulation apoptosis a variety mammalian cell types. In heart, disagreement persists concerning role that JNKs may play regulating apoptosis, since both pro- and antiapoptotic regulatory functions have reported cultured cardiomyocytes. Here we report first analysis cardiomyocyte death due to JNK inhibition or activation vivo using genetically modified mice. Three separate mouse models with selective were assessed for ventricular damage levels following ischemia-reperfusion injury. jnk1-/-, jnk2-/-, transgenic mice expressing dominant negative JNK1/2 within heart each shown less activity injury cellular To potentially address reciprocal gain-of-function phenotype associated sustained activation, generated express MKK7 heart. These displayed elevated cardiac but, ironically, also significantly protected from ischemia-reperfusion. Mechanistically, JNK-inhibited showed increased phosphorylation proapoptotic factor Bad at position 112, whereas decreased this site. Collectively, these results underscore complexity such elicit protection vivo, although probably through different mechanisms.