Oxidative stress and cardiovascular injury: Part I: basic mechanisms and in vivo monitoring of ROS

KK Griendling, GA FitzGerald - Circulation, 2003 - Am Heart Assoc
Circulation, 2003Am Heart Assoc
intracellularly, making it ideally suited to modify signaling pathways and gene expression.
The activity of the NAD (P) H oxidases can be modulated by vasoactive hormones and the
small molecular weight G-protein rac-1 (for review, see Griendling et al8). Angiotensin II,
tumor necrosis factor-α, thrombin, and platelet-derived growth factor all increase oxidase
activity and raise intracellular levels of O2· J and H2O2 in VSMCs. Angiotensin II and
lactosylceramide activate the endothelial cell enzyme, whereas fibroblasts increase O2· J …
intracellularly, making it ideally suited to modify signaling pathways and gene expression. The activity of the NAD (P) H oxidases can be modulated by vasoactive hormones and the small molecular weight G-protein rac-1 (for review, see Griendling et al8). Angiotensin II, tumor necrosis factor-α, thrombin, and platelet-derived growth factor all increase oxidase activity and raise intracellular levels of O2· J and H2O2 in VSMCs. Angiotensin II and lactosylceramide activate the endothelial cell enzyme, whereas fibroblasts increase O2· J production in response to angiotensin II, tumor necrosis factor-α, interleukin-1, and platelet-activating factor. Physical forces, including cell stretch, laminar shear stress, and the disturbed oscillatory flow that occurs at branch points, are also potent activators of O2· J production in endothelial cells. There are two major mechanisms by which hormones and physical forces activate the NAD (P) H oxidase:(1) acutely, whereby expressed enzyme is activated by phosphorylation, GTPase activity, and production of relevant lipid second messengers9; and (2) chronically, when expression of rate-limiting subunits of the enzyme is induced, thereby providing higher levels of enzyme susceptible to activation. 10 Macrophages are perhaps the major vascular source of O2· J in disease states. They oxidize LDL via activation of diverse enzymes. Neutrophils and monocytes may also secrete myeloperoxidase, which appears to initiate lipid peroxidation. 11 Two potential diffusible candidates to initiate myeloperoxidaseependent lipid peroxidation are tyrosyl radical and nitrogen dioxide (NO2). Deletion of myeloperoxidase reduces markedly the formation of F2-isoprostanes (F2iPs), quantitative indices of lipid peroxidation in vivo (vide infra) in an experimental model of peritonitis. 12
Am Heart Assoc