Regulation of the Phagocyte NADPH Oxidase by Rac GTPase

Increased vascular production of reactive oxygen species (ROS; termed oxidative stress) has been implicated in various chronic diseases, including hypertension. Oxidative stress is both a cause and a consequence of hypertension. Although oxidative injury may not be the sole etiology, it amplifies blood pressure elevation in the presence of other pro-hypertensive factors. Oxidative stress is a multisystem phenomenon in hypertension and involves the heart, kidneys, nervous system, vessels and possibly the immune system. Compelling experimental and clinical evidence indicates the importance of the vasculature in the pathophysiology of hypertension and as such much emphasis has been placed on the (patho)biology of ROS in the vascular system. A major source for cardiovascular, renal and neural ROS is a family of non-phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox), including the prototypic Nox2 homolog-based NADPH oxidase, as well as other Noxes, such as Nox1 and Nox4. Nox-derived ROS is important in regulating endothelial function and vascular tone. Oxidative stress is implicated in endothelial dysfunction, inflammation, hypertrophy, apoptosis, migration, fibrosis, angiogenesis and rarefaction, important processes involved in vascular remodeling in hypertension. Despite a plethora of data implicating oxidative stress as a causative factor in experimental hypertension, findings in human hypertension are less conclusive. This review highlights the importance of ROS in vascular biology and focuses on the potential role of oxidative stress in human hypertension.

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“…71,72 Activation also requires participation of Rac 2 (or Rac 1) and Rap 1A. In vascular cells, NADPH oxidase is constitutively active.…”

Section: Vascular Generation Of Rosmentioning

confidence: 99%

Reactive oxygen species and vascular biology: implications in human hypertension

2010

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“…Although Nox is implicated as the source of Ang II-induced ROS production (11,29,30), it has remained unclear which Nox isoforms are linked to AT 1 R. Vascular cells express Nox1, Nox2, and Nox4 (15). There are some hints for the functional coupling between Nox1 and AT 1 R; Nox1 is up-regulated upon Ang II stimulation of vascular smooth muscle cells (VSMCs) (31,32), Ang II fails to induce ROS production in Nox1-deficient VSMCs (31), and Ang II-mediated hypertension and blood pressure are decreased in Nox1-deficient mice (33,34).…”

Section: Multiple Homologs Of Gp91mentioning

confidence: 99%

Mechanism of Angiotensin II-induced Superoxide Production in Cells Reconstituted with Angiotensin Type 1 Receptor and the Components of NADPH Oxidase

Choi

Leto

Hunyady

et al. 2008

Journal of Biological Chemistry

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“…The NADPH oxidase, highly characterized in phagocytes, is a multicomponent enzyme complex that consists of the membrane-bound cytochrome b 558 (p22 phox and gp91 phox ) and cytoplasmic proteins (p40 phox , p47 phox , p67 phox ) that translocate to the membrane following cellular stimulation to produce superoxide (3,9,47). A multicomponent phagocyte-like NADPH oxidase is also a major source of ROS in many nonphagocytic cells, including mesangial cells.…”

mentioning

confidence: 99%

“…Rac1 is ubiquitously expressed, Rac2 is primarily expressed by cells of the hematopoietic lineage (20,28), while Rac3 is expressed primarily in the brain, nervous system, and mammary gland (6,36). Rac members are known to be key regulators of the actin cytoskeleton, as well as of the NADPH oxidase system, particularly Rac1 and Rac2 (3,22). In this context, Rac1 regulates gene expression, cell cycle progression, cell spreading, rearrangement of the actin cytoskeleton, and activation of the nonphagocytic NADPH (22), while Rac2, besides controlling actin-mediated functions, is necessary for activation of phagocytic NADPH oxidase (3,18).…”

mentioning

confidence: 99%

“…Rac members are known to be key regulators of the actin cytoskeleton, as well as of the NADPH oxidase system, particularly Rac1 and Rac2 (3,22). In this context, Rac1 regulates gene expression, cell cycle progression, cell spreading, rearrangement of the actin cytoskeleton, and activation of the nonphagocytic NADPH (22), while Rac2, besides controlling actin-mediated functions, is necessary for activation of phagocytic NADPH oxidase (3,18). The recent observation that fibroblasts lacking Rac1 upregulate Rac3 activation and cellular ROS suggests a potential role for this Rac family member in ROS synthesis (7).…”

mentioning

confidence: 99%

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Integrin α1β1 Controls Reactive Oxygen Species Synthesis by Negatively Regulating Epidermal Growth Factor Receptor-Mediated Rac Activation

Chen¹,

Abair²,

Ibanez³

et al. 2007

Molecular and Cellular Biology

100

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Integrins control many cell functions, including generation of reactive oxygen species (ROS) and regulation of collagen synthesis. Mesangial cells, found in the glomerulus of the kidney, are able to produce large amounts of ROS via the NADPH oxidase. We previously demonstrated that integrin ␣1-null mice develop worse fibrosis than wild-type mice following glomerular injury and this is due, in part, to excessive ROS production by ␣1-null mesangial cells. In the present studies, we describe the mechanism whereby integrin ␣1-null mesangial cells produce excessive ROS. Integrin ␣1-null mesangial cells have constitutively increased basal levels of activated Rac1, which result in its increased translocation to the cell membrane, excessive ROS production, and consequent collagen IV deposition. Basal Rac1 activation is a direct consequence of ligand-independent increased epidermal growth factor receptor (EGFR) phosphorylation in ␣1-null mesangial cells. Thus, our study demonstrates that integrin ␣1␤1-EGFR cross talk is a key step in negatively regulating Rac1 activation, ROS production, and excessive collagen synthesis, which is a hallmark of diseases characterized by irreversible fibrosis.Integrin ␣1␤1, a major collagen binding receptor, is expressed in different cell types, including fibroblasts (45), endothelial cells (8), and mesangial cells in the glomerulus of the kidney (30, 53). Integrin ␣1␤1 confers the ability of cells to bind to collagenous substrata, including collagens I and IV (4, 45), and to proliferate on these substrata (45). Moreover, cells expressing integrin ␣1␤1 sense extracellular levels of collagen and downregulate its synthesis at both transcriptional and translational levels (4,14). Finally, we demonstrated that integrin ␣1␤1 also downregulates the production of reactive oxygen species (ROS) (4, 58).Following renal injury, mice lacking integrin ␣1␤1 develop more extensive glomerular fibrosis characterized by excessive accumulation of collagen type IV compared to wild-type (WT) mice (4, 58). Increased fibrosis is due to both a direct effect of the lack of integrin ␣1␤1-mediated downregulation of collagen IV synthesis and excessive ROS production by ␣1-null mesangial cells.Constitutive production of ROS by mesangial cells, a major cell type found in the glomerulus of the kidney, originates from an intrinsic NADPH oxidase (26, 48) that normally functions at a low level and increases in response to inflammatory stimuli, high glucose, or stress (25,34,35,37,55). The NADPH oxidase, highly characterized in phagocytes, is a multicomponent enzyme complex that consists of the membrane-bound cytochrome b 558 (p22 phox and gp91 phox ) and cytoplasmic proteins (p40 phox , p47 phox , p67 phox ) that translocate to the membrane following cellular stimulation to produce superoxide (3, 9, 47). A multicomponent phagocyte-like NADPH oxidase is also a major source of ROS in many nonphagocytic cells, including mesangial cells. In the phagocyte-like NADPH oxidase, the catalytic subunits are termed Nox proteins, with ...

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Regulation of the Phagocyte NADPH Oxidase by Rac GTPase

Cited by 124 publications

References 122 publications

Reactive oxygen species and vascular biology: implications in human hypertension

Reactive oxygen species and vascular biology: implications in human hypertension

Mechanism of Angiotensin II-induced Superoxide Production in Cells Reconstituted with Angiotensin Type 1 Receptor and the Components of NADPH Oxidase

Integrin α1β1 Controls Reactive Oxygen Species Synthesis by Negatively Regulating Epidermal Growth Factor Receptor-Mediated Rac Activation

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