Nox 2 stimulates muscle differentiation via NF-κB/iNOS pathway

Piao, Yu Ji; Seo, Yong Hak; Hong, Feng; Kim, Jin Hwan; Kim, Young Joo; Kang, Myung Ho; Kim, Bum Shik; Jo, Sangmee Ahn; Jo, In-Ho; Jue, Dae Myung; Kang, Insug; Ha, Joohun; Kim, Sung Soo

doi:10.1016/j.freeradbiomed.2004.11.011

Cited by 80 publications

(85 citation statements)

References 51 publications

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“…Previously, we reported that ROS generated from Nox2 are involved in muscle differentiation. However, we observed that ROS levels were not completely decreased despite Nox2 knockdown, which also exhibited an incomplete suppression of muscle differentiation [20]. In addition, when the Nox1 subunit was specifically suppressed using siRNA, muscle differentiation was only slightly inhibited (data not shown).…”

Section: Discussionmentioning

confidence: 80%

Mitochondrial H2O2 generated from electron transport chain complex I stimulates muscle differentiation

et al. 2011

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Mitochondrial reactive oxygen species (mROS) have been considered detrimental to cells. However, their physiological roles as signaling mediators have not been thoroughly explored. Here, we investigated whether mROS generated from mitochondrial electron transport chain (mETC) complex I stimulated muscle differentiation. Our results showed that the quantity of mROS was increased and that manganese superoxide dismutase (MnSOD) was induced via NF-κB activation during muscle differentiation. Mitochondria-targeted antioxidants (MitoQ and MitoTEMPOL) and mitochondria-targeted catalase decreased mROS quantity and suppressed muscle differentiation without affecting the amount of ATP. Mitochondrial alterations, including the induction of mitochondrial transcription factor A and an increase in the number and size of mitochondria, and functional activations were observed during muscle differentiation. In particular, increased expression levels of mETC complex I subunits and a higher activity of complex I than other complexes were observed. Rotenone, an inhibitor of mETC complex I, decreased the mitochondrial NADH/NAD + ratio and mROS levels during muscle differentiation. The inhibition of complex I using small interfering RNAs and rotenone reduced mROS levels, suppressed muscle differentiation, and depleted ATP levels with a concomitant increase in glycolysis. From these results, we conclude that complex I-derived O 2 · − , produced through reverse electron transport due to enhanced metabolism and a high activity of complex I, was dismutated into H 2 O 2 by MnSOD induced via NF-κB activation and that the dismutated mH 2 O 2 stimulated muscle differentiation as a signaling messenger.

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Section: Discussionmentioning

confidence: 80%

Mitochondrial H2O2 generated from electron transport chain complex I stimulates muscle differentiation

et al. 2011

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“…(8,39,45). Those signal pathways may be involved in a myogenic response of the blood vessel (38,49).…”

Section: Discussionmentioning

confidence: 99%

NADPH oxidase has a directional response to shear stress

Godbole¹,

Lu²,

Guo³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Godbole AS, Lu X, Guo X, Kassab GS. NADPH oxidase has a directional response to shear stress. Am J Physiol Heart Circ Physiol 296: H152-H158, 2009. First published November 14, 2008 doi:10.1152/ajpheart.01251.2007.-Vessel regions with predilection to atherosclerosis have negative wall shear stress due to flow reversal. The flow reversal causes the production of superoxides (O 2 Ϫ ), which scavenge nitric oxide (NO), leading to a decrease in NO bioavailability and endothelial dysfunction. Here, we implicate NADPH oxidase as the primary source of O 2 Ϫ during full flow reversal. Nitrite production and the degree of vasodilation were measured in 46 porcine common femoral arteries in an ex vivo system. Nitrite production and vasodilation were determined before and after the inhibition of NADPH oxidase, xanthine oxidase, or mitochondrial oxidase. NADPH oxidase inhibition with gp91ds-tat or apocynin restored nitrite production and vasodilation during reverse flow. Xanthine oxidase inhibition increased nitrite production at the highest flow rate, whereas mitochondrial oxidase inhibition had no effect. These findings suggest that the NADPH oxidase system can respond to directional changes of flow and is activated to generate O 2 Ϫ during reverse flow in a dose-dependent fashion. These findings have important clinical implications for oxidative balance and NO bioavailability in regions of flow reversal in a normal and compromised cardiovascular system. superoxide; nitric oxide; oxidative balance; reduced nicotinamide adenine dinucleotide phosphate NITRIC OXIDE (NO) is released by endothelial cells to regulate blood vessel diameter acutely as well as to maintain long-term homeostatic conditions of the vessel wall (4,30). NO is produced in the endothelium from L-arginine by the enzyme endothelial NO synthase (eNOS) (4, 41) and is released in response to endothelial shear stress and other stimuli such as acetylcholine (4). Wall shear stress (WSS) has also been found to regulate the activity and expression of eNOS (34,40).Oscillatory and reverse WSS have negative effects on the endothelium due to superoxide (O 2 Ϫ ) production (14, 27, 28, 36, 52). It has been found that reverse flow in blood vessels causes reduced NO due to increased O 2 Ϫ production (36). Since NO is atheroprotective, regions of oscillatory and reverse WSS are more prone to atherosclerosis. Regions near branch points and curved vessels produce near-wall reverse flow (15,16).O 2 Ϫ can quickly inactivate NO, causing reduced NO bioavailability and endothelial dysfunction (9, 33). This endothelial dysfunction is implicated in atherosclerosis, hypertension, and heart failure (9,13,14,18,21). Reduced NO in the vessel wall impairs endothelium-dependent vasodilation, decreases inhibition of platelet and leukocyte adhesion, and is linked to the development of intimal hyperplasia (4, 21, 51). Our group has previously shown that NO production is reduced during reverse flow and that the addition of Tempol (an O 2 Ϫ scavenger) restored NO production in reverse flow to...

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“…We previously found that H 2 O 2 originating from Nox2 stimulates muscle differentiation via the NF-κB activation/iNOS expression pathway, and that PI3K is upstream of the Nox2/NF-κB/iNOS pathway [15,27,28]. As a npg result of increased iNOS expression, nitric oxide (NO) production was enhanced during muscle differentiation.…”

Section: C-ras Regulates Downstream Signaling Molecules Of Pi3kmentioning

confidence: 99%

“…Nox2 activity was analyzed as previously described [15]. Nox2 activity was determined indirectly by measuring the translocated amounts of p47 phox and Rac proteins forming the active NADPH oxidase to the plasma membrane via immunoblotting [15,54].…”

Section: Assays For Nox2 and Nf-κb Activitymentioning

confidence: 99%

“…Among them, PI3K seems to be a master molecule for muscle differentiation because it regulates all other molecules previously mentioned during muscle differentiation [13]. In addition, PI3K has been identified to activate NADPH oxidase, thus generating H 2 O 2 and leading to NF-κB activation, followed by increased expression of inducible nitric oxide synthase (iNOS) and subsequent NO generation during the myogenic process [14,15]. In contrast, the Raf/Mek/Erk pathway seems to suppress muscle differentiation [16].…”

Section: Introductionmentioning

confidence: 99%

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Proto-oncogenic H-Ras, K-Ras, and N-Ras are involved in muscle differentiation via phosphatidylinositol 3-kinase

et al. 2010

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Oncogenic H-Ras G12V and its variants have been shown to inhibit muscle differentiation. However, the role of proto-oncogenic Ras (c-Ras) in muscle differentiation remains unclear. The active GTP-bound form of Ras has been known to associate with diverse effectors including Raf, phosphatidylinositol 3-kinase (PI3K), Ral-GDS, and other molecules to transmit downstream signals. We hypothesize that c-Ras may stimulate muscle differentiation by selectively activating PI3K, an important mediator for muscle differentiation. In our experiments, inhibition of c-Ras by farnesyltransferase inhibitors and a dominant negative form of H-Ras (Ras S17N) suppressed muscle differentiation. Consistently, individual knockdown of H-Ras, K-Ras, and N-Ras by siRNAs all blocked muscle differentiation. Interestingly, we found that c-Ras preferentially interacts with PI3K rather than its major binding partner c-Raf, during myogenic differentiation, with total c-Ras activity remaining unchanged. PI3K and its downstream myogenic pathway, the Nox2/NF-κB/inducible nitric oxide synthase (iNOS) pathway, were found to be suppressed by inhibition of c-Ras activity during differentiation. Furthermore, expression of a constitutively active form of PI3K completely rescued the differentiation block and reactivated the Nox2/NF-κB/iNOS pathway in c-Ras-inhibited cells. On the basis of our results, we conclude that contrary to oncogenic Ras, proto-oncogenic H-Ras, K-Ras, and N-Ras are directly involved in the promotion of muscle differentiation via PI3K and its downstream signaling pathways. In addition, PI3K pathway activation is associated with a concurrent suppression of the otherwise predominantly activated Raf/ Mek/Erk pathway.

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Nox 2 stimulates muscle differentiation via NF-κB/iNOS pathway

Cited by 80 publications

References 51 publications

Mitochondrial H2O2 generated from electron transport chain complex I stimulates muscle differentiation

Mitochondrial H2O2 generated from electron transport chain complex I stimulates muscle differentiation

NADPH oxidase has a directional response to shear stress

Proto-oncogenic H-Ras, K-Ras, and N-Ras are involved in muscle differentiation via phosphatidylinositol 3-kinase

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