Role of NFkB and Other Transcription Factors

Expression of genes involved in the inflammatory response is controlled by activation of transcription factors, including NF-kB, AP-1, and HIF-1, which are activated by Ang II (113,114) (Fig. 3). NF-kB is particularly important in vascular inflammation, as many pro-inflammatory genes are under NF-kB control, including adhesion molecules (VCAM-1, ICAM-1), chemokines (MCP-1, RANTES), and cytokines (IL-6) (9). NF-kB also regulates Ang II and angiotensinogen gene expression thereby amplifying the

H2o2 And Adhesion Molecule

Fig. 3. Molecular mechanisms whereby Ang II induces inflammatory-reparative responses in the vascular wall. Ang II is a potent stimulator of NAD(P)H oxidase, which generates reactive oxygen species (ROS), such as and H2O2. These effects are mediated through PKC, PLD, and c-Src. Increased intracellular ROS formation stimulates activation of redox-sensitive transcription factors, including NF-kB, AP-1, and HIF-1, which in turn activate pro-inflammatory genes to produce cytokines and chemokines and to induce expression of cell adhesion molecules. Ang II also activates MAP kinases, tyrosine kinases, and RhoA/Rho kinase, which stimulate cell growth and fibrogenic pathways. AP-1, activator protein-1; CAM, cell adhesion molecules; CTGF, connective tissue growth factor; e", electron; HIF-1, hypoxia inducible factor-1; ICAM-1, intercellular cell adhesion molecule; IL, interleukin; MAP, mitogen-activated protein; MCP-1, monocyte chemoattractant protein-1; NF-kB, nuclear factor kB; PECAM, platelet-endothelial cell adhesion molecule; PKC, protein kinase C; PLD, phospholipase D; TGF-ß, transforming growth factor-ß; TNF-a, tumor necrosis factor a; VCAM, vascular cell adhesion molecule.

Fig. 3. Molecular mechanisms whereby Ang II induces inflammatory-reparative responses in the vascular wall. Ang II is a potent stimulator of NAD(P)H oxidase, which generates reactive oxygen species (ROS), such as and H2O2. These effects are mediated through PKC, PLD, and c-Src. Increased intracellular ROS formation stimulates activation of redox-sensitive transcription factors, including NF-kB, AP-1, and HIF-1, which in turn activate pro-inflammatory genes to produce cytokines and chemokines and to induce expression of cell adhesion molecules. Ang II also activates MAP kinases, tyrosine kinases, and RhoA/Rho kinase, which stimulate cell growth and fibrogenic pathways. AP-1, activator protein-1; CAM, cell adhesion molecules; CTGF, connective tissue growth factor; e", electron; HIF-1, hypoxia inducible factor-1; ICAM-1, intercellular cell adhesion molecule; IL, interleukin; MAP, mitogen-activated protein; MCP-1, monocyte chemoattractant protein-1; NF-kB, nuclear factor kB; PECAM, platelet-endothelial cell adhesion molecule; PKC, protein kinase C; PLD, phospholipase D; TGF-ß, transforming growth factor-ß; TNF-a, tumor necrosis factor a; VCAM, vascular cell adhesion molecule.

Ang II-mediated inflammatory cascade (115,116). NF-kB is a family of highly inducible DNA-binding proteins regulated by protein processing and by association with the cytoplasmic inhibitor, IkB (117). Ang II influences the NF-kB activation pathway at multiple levels in VSMCs (117). It stimulates translocation to the nucleus, DNA-binding, transcription of a NF-kB reporter gene and IkB degradation (114,117). Presence of other inflammatory mediators, such as IL-1^, may be necessary for Ang II to fully activate NF-kB in VSMCs (118).

The importance of NF-kB to inflammatory molecule expression is evidenced by in vitro studies demonstrating that the inhibition of NF-kB activation prevents Ang II-induced expression of IL-6, VCAM-1 and MCP-1 (114,115). NF-kB activation is also essential for Ang II-dependent proliferation and migration of VSMCs, because SN50, selective NF-kB inhibitor; phenethyl caffeinate, inhibitor of NF-kB nuclear translocation; and Bay 11-7085, inhibitor of IkB phosphorylation effectively arrest Ang II-dependent DNA synthesis and migration (119). Both ATjR and AT2R have been implicated in these processes.

In Ang II-infused animals, NF-kB activation is increased and expression of cytokines (TNF-a, IL-6) and chemokines (MCP-1) is augmented (120). In experimental models of atherosclerosis, renal injury, and in pulmonary hypertension, ACE inhibitors reduce tissue NF-kB activity, decrease cytokine and chemokine expression, and prevent vascular and renal inflammation (121-123). In a model of Ang II-dependent severe hypertension with end-organ damage, leukocyte infiltration in the vascular wall accompanies vascular PAI-1, MCP-1, iNOS, and Tissue Factor overexpression, and NF-kB activation (124). These effects were directly associated with NF-kB activation, because NF-kB inhibition by pyrrolidine dithiocarbamate decreased blood pressure, reduced cardiac hypertrophy, and ameliorated vascular injury in small renal and cardiac vessels (124). These findings suggest that NF-kB is a major inducer of Ang II-mediated upregulation of adhesion molecules and cytokine expression.

Ang II regulation of NF-kB involves ROS, since antioxidants interfere with its activation by Ang II (125,126). ROS-induced NF-kB activation probably occurs through redox modification of reactive cysteines (127). Upstream kinase(s) and/or phosphatase(s) prone to thiolation or oxidation of SH groups are possible candidates mediating redox regulation. In particular, thioredoxin and Redox-factor-1 (Ref-1) are important activators of NF-kB (128).

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