Cytoskeleton‐dependent activation of the inducible nitric oxide synthase in cultured aortic smooth muscle cells

Marczin, Nándor; Jilling, Tamás; Papapetropoulos, Andreas; Go, Carolyn Y.; Catravas, John D.

doi:10.1111/j.1476-5381.1996.tb15510.x

Cited by 33 publications

(18 citation statements)

References 62 publications

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“…There is overwhelming evidence linking cytoskeletal integrity to gene regulation, and a growing interest in iNOS regulation by the cytoskeleton (41). Disruption of the actin cytoskeleton upregulates iNOS expression in vascular smooth muscle cells (42).…”

Section: Discussionmentioning

confidence: 99%

Inducible Nitric Oxide Synthase Contributes to Ventilator-induced Lung Injury

Peng

Abdulnour

Sammani

et al. 2005

Am J Respir Crit Care Med

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Rationale: Inducible nitric oxide synthase (iNOS) has been implicated in the development of acute lung injury. Recent studies indicate a role for mechanical stress in iNOS and endothelial NOS (eNOS) regulation. Objectives: This study investigated changes in lung NOS expression and activity in a mouse model of ventilatorinduced lung injury. Methods: C57BL/6J (wild-type [WT]) and iNOSdeficient (iNOS Ϫ/Ϫ ) mice received spontaneous ventilation (control) or mechanical ventilation (MV; VT of 7 and 20 ml/kg) for 2 hours, after which NOS gene expression and activity were determined and pulmonary capillary leakage assessed by the Evans blue albumin assay. Results: iNOS mRNA and protein expression was absent in iNOS Ϫ/Ϫ mice, minimal in WT control mice, but significantly upregulated in response to 2 hours of MV. In contrast, eNOS protein was decreased in WT mice, and nonsignificantly increased in iNOS Ϫ/Ϫ mice, as compared with control animals. iNOS and eNOS activities followed similar patterns in WT and iNOS Ϫ/Ϫ mice. MV caused acute lung injury as suggested by cell infiltration and nitrotyrosine accumulation in the lung, and a significant increase in bronchoalveolar lavage cell count in WT mice, findings that were reduced in iNOS Ϫ/Ϫ mice. Finally, Evans blue albumin accumulation in lungs of WT mice was significant (50 vs. 15% increase in iNOS Ϫ/Ϫ mice compared with control animals) in response to MV and was prevented by treatment of the animals with the iNOS inhibitor aminoguanidine. Conclusion: Taken together, our results indicate that iNOS gene expression and activity are significantly upregulated and contribute to lung edema in ventilator-induced lung injury.Keywords: inducible nitric oxide synthase; lung permeability; mechanical ventilation Nitric oxide (NO) is involved in many physiologic and pathologic conditions, such as blood vessel relaxation, neurotransmission, and host defense. NO also plays a critical role in tissue injury in the context of various inflammatory conditions (1). NO is produced by three isoforms (neuronal, endothelial, and inducible) of NO synthase (NOS). Endothelial NOS (eNOS), which is calcium/calmodulin (Ca 2ϩ /CaM)-dependent and activated by agonists (e.g., acetylcholine), produces a low level of NO output, whereas inducible NOS (iNOS) is independent of Ca 2ϩ /CaM, is transcriptionally regulated by proinflammatory products (e.g., LPS) and cytokines (interleukin 1␤ [IL-1␤], tumor necrosis factor ␣ [TNF-␣], IFN-␥), and results in sustained and elevated (Received in original form November 19, 2004; accepted in final form May 20, 2005) Supported by awards from the National Heart, Lung, and Blood Institute (NIH R01 HL049441 and P50 HL 73994).* These authors contributed equally to the work presented in this article. release of NO (2). Therefore, overproduction of NO, in particular in the setting of superoxide production (3), leads to oxidative stress and tissue injury in conditions such as endotoxin-induced acute lung injury (ALI) (4).ALI is characterized by a severe inflammatory process, pr...

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Section: Discussionmentioning

confidence: 99%

Inducible Nitric Oxide Synthase Contributes to Ventilator-induced Lung Injury

Peng

Abdulnour

Sammani

et al. 2005

Am J Respir Crit Care Med

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“…The separated proteins were transferred to a PVDF membrane (Hybond ECL, Amersham Pharmacia, Freiburg, Germany) using a Bio-Rad Mini protean tank blot equipment (21). The membranes were blocked with 5%-non-fat milk (ICN) in 2 M Tris buffered saline (TBS) with 0.1% Tween-20 (ICN) for one hour at room temperature and subsequently exposed to a polyclonal rabbit anti-iNOS antibody 1/1000 (Santa Cruz Biotechnology, Santa Cruz, CA) at room temperature for 1 h in blocking solution.…”

Section: Western Blotmentioning

confidence: 99%

Effects of human cathelicidin antimicrobial peptide LL‐37 on lipopolysaccharide‐induced nitric oxide release from rat aorta in vitro

Ciornei

Egesten

Bodelsson

2003

Acta Anaesthesiol Scand

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Background: Lipopolysaccharides (LPS), released by Gram‐negative bacteria, cause vascular expression of inducible nitric oxide synthase (iNOS) leading to nitric oxide (NO) production and septic shock. Human cathelicidin antimicrobial peptide (LL‐37) can bind and neutralize LPS. We wanted to study whether LL‐37 affects LPS or interleukin‐1β (IL‐1β)‐induced production, release and function of NO in intact rat aorta rings and cultured rat aorta smooth muscle cells.Methods: Isolated segments of thoracic aorta and cultured cells were incubated in the presence of LPS, LL‐37, LPS + IL‐37, IL‐1β, IL‐1β + IL‐37 or in medium alone. Smooth muscle contraction in response to phenylephrine and accumulation of the sdegradation products of NO, nitrate and nitrite, were measured on aorta segments. Levels of iNOS were assessed by Western blot and cytotoxic effects were detected by measurement of DNA fragmentation in cultured cells. Number of viable cells were determined after Trypan blue treatment.Results: Both LPS and IL‐1β reduced contractility in response to phenylephrine and increased NO production as well as iNOS expression. LL‐37 inhibited the LPS depression of vascular contractility induced only by LPS. LL‐37 reduced both the LPS‐ and IL‐1β‐induced NO production and iNOS expression. LL‐37 at high concentrations induced DNA fragmentation and decreased the number of living cells.Conclusion: IL‐37 reduces NO production induced by LPS and IL‐1β. The reduction does not seem to result only from neutralization of LPS but also from a cytotoxic effect, possibly via induction of apoptosis.

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“…Several isoforms of NOS have been identified, including the endothelial form of NOS (eNOS), which requires Ca 2ϩ /calmodulin (Fulton et al, 1999), and the inducible Ca 2ϩ /calmodulin-independent form of NOS (iNOS) (Nathan and Xie, 1994;Fleming et al, 1997). iNOS is expressed mainly in macrophages (Stuehr and Marletta, 1985;Nathan, 1997) and other cell types, including endothelial cells, cardiac myocytes, vascular smooth muscle cells, hepatocytes, and mesangial cells (Geller et al, 1993;Shultz et al, 1994;Iwashina et al, 1996;Marczin et al, 1996). The transcriptional and translational regulation of iNOS in various cell types can be induced by cytokines, growth factors, and endotoxins [i.e., lipopolysaccharide (LPS)] (Lamas et al, 1992;Xie et al, 1992;Wang and Marsden, 1995).…”

Section: Introductionmentioning

confidence: 99%

Salvianolic Acid B Exerts Vasoprotective Effects through the Modulation of Heme Oxygenase-1 and Arginase Activities

Joe¹,

Zheng²,

Kim³

et al. 2012

J Pharmacol Exp Ther

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Salvia miltiorrhiza (Danshen), a traditional Chinese herbal medicine, is commonly used for the prevention and treatment of cardiovascular disorders including atherosclerosis. However, the mechanisms responsible for the vasoprotective effects of Danshen remain largely unknown. Salvianolic acid B (Sal B) represents one of the most bioactive compounds that can be extracted from the water-soluble fraction of Danshen. We investigated the effects of Danshen and Sal B on the inflammatory response in murine macrophages. Danshen and Sal B both induced the expression of heme oxygenase-1 (HO-1) and inhibited nitric oxide (NO) production and inducible NO synthase (iNOS) expression in lipopolysaccharide (LPS)-activated RAW 264.7 cells. Inhibition of HO activity using Sn-protoporphyrin-IX (SnPP) abolished the inhibitory effect of Sal B on NO production and iNOS expression. Sal B increased macrophage arginase activity in a dose-dependent manner and diminished LPS-inducible tumor necrosis factor-␣ production. These effects were also reversed by SnPP. These data suggest that HO-1 expression plays an intermediary role in the anti-inflammatory effects of Sal B. In contrast to the observations in macrophages, Sal B dose-dependently inhibited arginase activity in murine liver, kidney, and vascular tissue. Furthermore, Sal B increased NO production in isolated mouse aortas through the inhibition of arginase activity and reduction of reactive oxygen species production. We conclude that Sal B improves vascular function by inhibiting inflammatory responses and promoting endotheliumdependent vasodilation. Taken together, we suggest that Sal B may represent a potent candidate therapeutic for the treatment of cardiovascular diseases associated with endothelial dysfunction.

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Cytoskeleton‐dependent activation of the inducible nitric oxide synthase in cultured aortic smooth muscle cells

Cited by 33 publications

References 62 publications

Inducible Nitric Oxide Synthase Contributes to Ventilator-induced Lung Injury

Inducible Nitric Oxide Synthase Contributes to Ventilator-induced Lung Injury

Effects of human cathelicidin antimicrobial peptide LL‐37 on lipopolysaccharide‐induced nitric oxide release from rat aorta in vitro

Salvianolic Acid B Exerts Vasoprotective Effects through the Modulation of Heme Oxygenase-1 and Arginase Activities

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