Nox regulation of smooth muscle contraction

Ritsick, Darren R.; Edens, William A.; Finnerty, Victoria; Lambeth, J. David

doi:10.1016/j.freeradbiomed.2007.03.006

Cited by 60 publications

(55 citation statements)

References 48 publications

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“…This was confirmed in our studies with VAS2870, a NOX1/4 inhibitor that had no effect on feeding‐stimulated peristaltic contractions. The biological importance of Nox5 in smooth muscle contraction was also shown in Drosophila melanogaster , where depletion of Nox5 (dNox) in the musculature was studied using RNA interference approaches 50. dNox‐RNAi Drosophila exhibited retention of mature eggs, impaired ovarian muscle contractions, and sterility attributed to altered agonist‐induced calcium flux and decreased muscle contraction.…”

Section: Discussionmentioning

confidence: 94%

NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

Montezano

Camargo

Persson

et al. 2018

JAHA

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BackgroundNADPH Oxidase 5 (Nox5) is a calcium‐sensitive superoxide‐generating Nox. It is present in lower forms and higher mammals, but not in rodents. Nox5 is expressed in vascular cells, but the functional significance remains elusive. Given that contraction is controlled by calcium and reactive oxygen species, both associated with Nox5, we questioned the role of Nox5 in pro‐contractile signaling and vascular function.Methods and ResultsTransgenic mice expressing human Nox5 in a vascular smooth muscle cell–specific manner (Nox5 mice) and Rhodnius prolixus, an arthropod model that expresses Nox5 endogenoulsy, were studied. Reactive oxygen species generation was increased systemically and in the vasculature and heart in Nox5 mice. In Nox5‐expressing mice, agonist‐induced vasoconstriction was exaggerated and endothelium‐dependent vasorelaxation was impaired. Vascular structural and mechanical properties were not influenced by Nox5. Vascular contractile responses in Nox5 mice were normalized by N‐acetylcysteine and inhibitors of calcium channels, calmodulin, and endoplasmic reticulum ryanodine receptors, but not by GKT137831 (Nox1/4 inhibitor). At the cellular level, vascular changes in Nox5 mice were associated with increased vascular smooth muscle cell [Ca2+]i, increased reactive oxygen species and nitrotyrosine levels, and hyperphosphorylation of pro‐contractile signaling molecules MLC20 (myosin light chain 20) and MYPT1 (myosin phosphatase target subunit 1). Blood pressure was similar in wild‐type and Nox5 mice. Nox5 did not amplify angiotensin II effects. In R. prolixus, gastrointestinal smooth muscle contraction was blunted by Nox5 silencing, but not by VAS2870 (Nox1/2/4 inhibitor).ConclusionsNox5 is a pro‐contractile Nox isoform important in redox‐sensitive contraction. This involves calcium‐calmodulin and endoplasmic reticulum–regulated mechanisms. Our findings define a novel function for vascular Nox5, linking calcium and reactive oxygen species to the pro‐contractile molecular machinery in vascular smooth muscle cells.

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Section: Discussionmentioning

confidence: 94%

NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

Montezano

Camargo

Persson

et al. 2018

JAHA

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“…NAD(P)H oxidases have been linked to a variety of cellular functions, including proliferation, migration, hypertrophy, regulation of metalloproteinases, matrix synthesis, cell senescence, and contraction. 28,29,36,[52][53][54] Indeed, differential roles of Nox1 and Nox4 in vascular smooth muscle cells have been correlated with differential compartmentalization in specific signaling domains in the membrane and focal adhesions. 55 Such observations combined with the differential expression of multiple Nox proteins in vascular smooth muscle in vitro and during restenosis 56 suggest distinct functions for these proteins.…”

Section: Discussionmentioning

confidence: 99%

NAD(P)H Oxidase Mediates TGF-β1–Induced Activation of Kidney Myofibroblasts

Bondi¹,

Manickam²,

Lee³

et al. 2010

Journal of the American Society of Nephrology

266

267

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TGF-␤1 expression closely associates with activation and conversion of fibroblasts to a myofibroblast phenotype and synthesis of an alternatively spliced cellular fibronectin variant, Fn-ED-A. Reactive oxygen species (ROS), such as superoxide, which is a product of NAD(P)H oxidase, also promote the transition of fibroblasts to myofibroblasts, but whether these two pathways are interrelated is unknown. Here, we examined a role for NAD(P)H oxidase-derived ROS in TGF-␤1-induced activation of rat kidney fibroblasts and expression of ␣-smooth muscle actin (␣-SMA) and Fn-ED-A. In vitro, TGF-␤1 stimulated formation of abundant stress fibers and increased expression of both ␣-SMA and Fn-ED-A. In addition, TGF-␤1 increased both the activity of NADPH oxidase and expression of Nox2 and Nox4, homologs of the NAD(P)H oxidase family, indicating that this growth factor induces production of ROS. Small interfering RNA targeted against Nox4 markedly inhibited TGF-␤1-induced stimulation of NADPH oxidase activity and reduced ␣-SMA and Fn-ED-A expression. Inhibition of TGF-␤1 receptor 1 blocked Smad3 phosphorylation; reduced TGF-␤1-enhanced NADPH oxidase activity; and decreased expression of Nox4, ␣-SMA, and Fn-ED-A. Diphenyleneiodonium, an inhibitor of flavin-containing enzymes such as the Nox oxidases, had no effect on TGF-␤1-induced Smad3 but reduced both ␣-SMA and Fn-ED-A protein expression. The Smad3 inhibitor SIS3 reduced NADPH oxidase activity, Nox4 expression, and blocked ␣-SMA and Fn-ED-A, indicating that stimulation of myofibroblast activation by ROS is downstream of Smad3. In addition, TGF-␤1 stimulated phosphorylation of extracellular signal-regulated kinase (ERK1/2), and this was inhibited by blocking TGF-␤1 receptor 1, Smad3, or the Nox oxidases; ERK1/2 activation increased ␣-SMA and Fn-ED-A. Taken together, these results suggest that TGF-␤1-induced conversion of fibroblasts to a myofibroblast phenotype involves a signaling cascade through Smad3, NAD(P)H oxidase, and ERK1/2.

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“…A prominent cardiovascular effect of Nox1, which is primarily expressed in vascular smooth muscle, is to potentiate the pressor response to angiotensin II (20,26). Orthologs of Nox5 in Drosophila have been shown to increase smooth muscle contraction through the formation of hydrogen peroxide (58). Collectively these findings suggest that Nox5 is expressed in vascular tissue and may contribute to a number of physiological functions, as well as diseases of the cardiovascular system.…”

Section: Smooth Musclementioning

confidence: 96%

“…In contrast, the increased hsp90 binding induced by Nox5 may actually prevent eNOS uncoupling and provide increased NO output to compensate for the reduced ability to activate NO-sensitive pathways. Another possible mechanism for the increase in eNOS activity could be due to the ROS-stimulated elevation of intracellular calcium (58), and calcium-activated calmodulin is the primary mechanism for eNOS activation (25) (Fig. 3).…”

Section: Nox5 and Regulation Of Cellular Functionmentioning

confidence: 99%

Nox5 and the Regulation of Cellular Function

Fulton

2009

Antioxidants & Redox Signaling

137

142

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The NADPH oxidase (Nox) family of enzymes is comprised of seven members, Noxes 1-5 and the Duoxes 1 and 2. Nox5 was the last of the conventional Nox enzymes to be identified, and in comparison to its siblings, much less is known about its molecular regulation and even less regarding its functional significance. The loss of Nox5 from rodent genomes has contributed significantly to this deficit in knowledge, but recent discoveries have narrowed the gap. There are many differences between Nox5 and the other Nox isoforms including alternative splicing, transcriptional regulation, enzymatic control mechanisms, tissue distribution, and intracellular trafficking. The goal of this review is to outline recent advances in our knowledge of the genetic regulation, the molecular mechanisms governing its activity, and the functional significance of Nox5 in human physiology and pathophysiology. Antioxid. Redox Signal. 11, 2443-2452.

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Nox regulation of smooth muscle contraction

Cited by 60 publications

References 48 publications

NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

NAD(P)H Oxidase Mediates TGF-β1–Induced Activation of Kidney Myofibroblasts

Nox5 and the Regulation of Cellular Function

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