OXIDANT-MEDIATED ACTIVATION OF MITOGEN-ACTIVATED PROTEIN-KINASES AND NUCLEAR TRANSCRIPTION FACTORS IN THE CARDIOVASCULAR-SYSTEM - A BRIEF OVERVIEW

In response to oxidant stress, the cardiovascular system is known to e xpress a number of genes, which could occur owing to the participation of mitogen-activated protein kinases such as MAPKs, ERK and JNK (SAPK ) followed by stimulation of at least two well-defined transcription f actors NF-KB and AP-1 (c-Fos and c-Jun). Oxidants activate cytosolic a nd membrane-bound PLA; activities with thr subsequent production of AA metabolites such as HETEs, which subsequently stimulate ERK and JNK ( SAPK) activities leading to the activation of transcriptional factors and the ultimate stimulation of the transcription of several mitogen-s tress-responsive genes. LacCer, a ceramide analogue present in atheros clerotic plaques, has been found to induce proliferation of aortic smo oth muscle cells. LacCer is involved in Ras-GTP loading, activation of kinase cascades (MEK, Raf, p44 MAPK) and c-fos expression. TNF-alpha, on the other hand, induces c-fos, c-myc and c-jun expression. Recent investigations link ceramide and its analogues to the extracellular si gnal-regulated kinase (ERK) cascade, stress-activated protein kinase-c -Jun kinase (SAPK/JNK) cascade and apoptotic responses. These critical steps in the signalling pathways are sensitive to intracellular thiol -redox and protease(s)-antiprotease(s) status, both of which can be mo dified by oxidants. Because mobilisation oi intracellular Ca2+ caused by a variety oi signals also plays a role in thr activation of the sig nalling pathways, an important aspect of future work will be to ascert ain the roles of oxidants and Ca2+ individually and in combination in the activation of the signalling pathways. The following two important questions also deserve future attention: (1) How does NF-kB shield ce lls from apoptotic death? and (2) By what mechanisms does the activate d NF-kB cause cellular transformation! Fur thermore, the role oi AP-1 acting as transcriptional activator seems clear, but thr target genes remain to be defined. CELL SIGNAL 10;10:675-683, 1998. (C) 1998 Elsevi er Science Inc.