Multiple role of reactive oxygen species in the arterial wall

Increased oxidative stress plays an important role in vascular dysfunction and atherogenesis. Both systemic factors, such as hypercholesterolemia and hyperglycemia, and local factors, such as activation of macrophages and T c ells, may contribute to oxidative stress. Oxidation of lipids in lipoprotei ns and cell membranes leads to functionally important modifications of prot eins that affect their recognition by cell surface receptors and protein-pr otein interactions within the cell, including DNA binding. Oxidized LDL and extracellular oxidation modulate oxidation-sensitive signaling pathways, b ut it is not clear to what extent this results from receptor-mediated activ ation or from direct effects on the intracellular redox-balance. Extensive evidence indicates that reactive oxygen species (ROS) regulate gene express ion by modulating a large number of transcription factors, including the nu clear transcription factor kappa B (NF kappaB), the peroxisome proliferator activated receptory (PPAR gamma), and pathways linked to apoptosis. It is also increasingly recognized that cell differentiation and proliferation, c ytokine expression, and programmed cell death are determined by the interac tions between oxidation-sensitive regulatory pathways previously thought to lead to distinct outcomes. Because hypercholesterolemia exerts pro-oxidant effects both intra- and extracellularly and because increased ROS formatio n affects vascular reactivity and atherogenesis by modulating multiple sign aling pathways and transcriptional events, future investigations of its ath erogenic mechanisms should place greater emphasis on the net effect of such modulation on the expression of a large spectrum of genes. One way of doin g this will be by defining clusters of genes responding to hypercholesterol emic stimuli-or interventions with structurally unrelated antioxidants-in a nalogous ways, irrespective of what regulatory pathway they are controlled by. Microarray technologies that allow simultaneous assessment of large num bers of genes may provide a tool for this approach. (C) 2001 Wiley-Liss, In c.