Cell. Signal. Vol. 10, No. 10, pp. 675–683, 1998 ISSN 0898-6568/98 $19.00 Copyright  1998 Elsevier Science Inc. PII S0898-6568(98)00014-X TOPICAL REVIEW Oxidant-Mediated Activation of Mitogen- Activated Protein Kinases and Nuclear Transcription Factors in the Cardiovascular System: A Brief Overview Sajal Chakraborti* and Tapati Chakraborti Department of Biochemistry and Biophysics, University of Kalyani, Kalyani 741235, West Bengal, India ABSTRACT. In response to oxidant stress, the cardiovascular system is known to express 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 factors NF-KB and AP-1 (c-Fos and c-Jun). Oxidants activate cytosolic and membrane-bound PLA 2 activities with the 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–stress- responsive genes. LacCer, a ceramide analogue present in atherosclerotic plaques, has been found to induce pro- liferation of aortic smooth muscle cells. LacCer is involved in Ras-GTP loading, activation of kinase cascades (MEK, Raf, p44 MAPK) and c-fos expression. TNF-, on the other hand, induces c-fos, c-myc and c-jun expres- sion. Recent investigations link ceramide and its analogues to the extracellular signal-regulated kinase (ERK) cascade, stress-activated protein kinase–c-Jun kinase (SAPK/JNK) cascade and apoptotic responses. These criti- cal steps in the signalling pathways are sensitive to intracellular thiol–redox and protease(s)–antiprotease(s) sta- tus, both of which can be modified by oxidants. Because mobilisation of intracellular Ca 2+ caused by a variety of signals also plays a role in the activation of the signalling pathways, an important aspect of future work will be to ascertain the roles of oxidants and Ca 2 + 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 cells from apoptotic death? and (2) By what mechanisms does the activated NF-kB cause cellular transformation? Fur- thermore, the role of AP-1 acting as transcriptional activator seems clear, but the target genes remain to be de- fined. cell signal 10;10:675–683, 1998.  1998 Elsevier Science Inc. KEY WORDS. Oxidant, Antioxidant, Thiol, Protease, Antiprotease, Phosphorylation, Signal transduction, Mitogen-activated protein kinase, Nuclear transcription factor, Cardiovascular system, Ischaemia-reperfusion, Heat shock proteins, Ceramide, Lactosyl ceramide, Apoptosis, Atherosclerosis INTRODUCTION (MAPKs). In multicellular eukaryotes, this MAPK pathway is activated by ligand binding to receptor-associated tyro- The transmission of extracellular signals to their intracellu- sine kinases (RTKs) and requires the activation of small lar targets is mediated by a network of interacting proteins GTP-binding proteins; that is, Ras through adaptor mole- that governs a large number of cellular processes. It is likely cules—for instance, GRB-2 (an adaptor protein that func- that most, and perhaps all, eukaryotic cells contain kinase tions downstream from RTKs but upstream of Ras in mam- cascades that activate mitogen-activated protein kinases malian cells) and such guanine nucleotide exchange factors (GEFs) as, for example, SOS [1–4] (Fig. 1). This activation *Author to whom all correspondence should be addressed. E-mail: sajal@ klyuniv.ernet.in is followed by sequential stimulation of several cytoplasmic ki- Abbreviations: MAPK–mitogen-activated protein kinase; ROS–reactive nases that are collectively known as MAPKs (Fig. 2). Eventu- oxygen species; EGF–epidermal growth factor; NGF–nerve growth factor; ally, this phosphorylation cascade activates a set of regulatory MAP2K–MAPK kinase; MEKK–MEK kinase; PKC–protein kinase C; GSK– glycogen synthase kinase; RSK–ribosomal S6 kinase; MEK–mitogen-activated molecules that initiate cell proliferation. Signalling MAPK ERK-activating kinase; PEST domain–Pro-, Glu-, Ser-, Thr-rich domain of enzymes are referred to by the general names MAP3K, IkB; SAPK–stress-activated protein kinase; Trx–thioredoxin; JNK–c-Jun NH 2 MAP2K and MAPK [5], and the groups of isoforms serving in terminal kinase; ERK–extracellular signal-regulated kinase; RPTK–receptor protein tyrosine kinase; PLA 2 –phospholipase A 2 ; AA–arachidonic acid; Egr– each signalling pathway at the same level may also be desig- early growth response transcription factor; NF-kB–nuclear factor kB; IkB– nated by distinct names—for example, extracellular signal-reg- inhibitory kB; Ras–a small GTP-binding protein; GRB-2–an adaptor mole- ulated kinase (ERK) for MAPK [5]. cule; SOS–a guanine nucleotide exchange factor (GEF). Received 19 September 1997; and accepted 9 February 1998. As a central component of the MAPK cascade, the acti-