Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation

Ignarro, Louis J.; Buga, Georgette M.; Liu, Wei; Bauer, Philip M.; Wu, Guoyao; Soldato, Piero Del

doi:10.1073/pnas.071054698

Cited by 309 publications

(246 citation statements)

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“…This activity of NO ⅐ has been ascribed to both cGMP-dependent and -independent mechanisms. Experiments in rodents have found, with a few notable exceptions (18,30), that NO ⅐ controls the cell cycle through cGMP. In contrast, the anti-proliferation effects of NO ⅐ in human cells have been more frequently associated with cGMP-independent signaling (29,31).…”

Section: Discussionmentioning

confidence: 99%

“…Nitric oxide (NO ⅐ ) regulates a wide range of cellular activities including gene expression (12)(13)(14)(15)(16), cell proliferation (17,18), and apoptosis (19) that are closely linked to its anti-tumor and anti-atherosclerotic properties (17,20). Using a microarraybased approach in soluble guanylate cyclase-deficient cells, we recently demonstrated that NO ⅐ predominately regulated a large set of cell cycle genes independent cGMP (15).…”

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confidence: 99%

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Nitric Oxide Down-regulates Polo-like Kinase 1 through a Proximal Promoter Cell Cycle Gene Homology Region

Zhang

Wang

Kern

et al. 2007

Journal of Biological Chemistry

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Polo-like kinase 1 (PLK1) is an evolutionarily conserved serine/threonine kinase essential for cell mitosis. As a master cell cycle regulator, p21/Waf1 plays a critical role in cell cycle progression. Nitric oxide (NO ⅐ ) has been shown to down-regulate PLK1 and up-regulate p21/Waf1 independent of cGMP. Here, the respective roles of p38 MAPK and p21/Waf1 in NO ⅐ -mediated PLK1 repression were investigated using differentiated U937 cells that lack soluble guanylate cyclase. NO ⅐ was shown to down-regulate both PLK1 mRNA and protein. Nuclear run-on assays and mRNA stability studies demonstrated that the effect of NO ⅐ on PLK1 expression was associated with decreased transcription without changes in transcript stability. SB202190, a p38 MAPK inhibitor, prevented transcriptional repression of PLK1 by NO ⅐ . Transfection with dominant-negative p38 MAPK mutant eliminated the NO ⅐ effect on both p21/Waf1 and PLK1 gene expression. Knockdown of p21/Waf1 with siRNA also substantially reduced the regulatory effect of NO ⅐ on PLK1. Reporter gene experiments showed that NO ⅐ decreased activity of the PLK1 proximal promoter, an effect that was blocked by p38 MAPK inhibitor. Deletion or mutation of the CDE/CHR promoter site, an element regulated by p21/Waf1, increased base-line promoter activity and abolished NO ⅐ repression of the PLK1 promoter. Likewise, electrophoretic mobility shift assays with CDE/CHR probe revealed a NO ⅐ -mediated change in protein-probe complex formation. Competition with various unlabeled CDE/CHR mutant sequences showed that NO ⅐ increased nuclear protein binding to intact CHR. These results demonstrate that a NO ⅐ -p38 MAPK-p21/Waf1 signal transduction pathway represses PLK1 through a canonical CDE/CHR promoter element.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Nitric Oxide Down-regulates Polo-like Kinase 1 through a Proximal Promoter Cell Cycle Gene Homology Region

Zhang

Wang

Kern

et al. 2007

Journal of Biological Chemistry

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“…Arginase I is considered the hepatic isoform catalyzing the final step in the urea cycle, and its expression can be induced by hypoxia and lipopolysaccharide 5. Arginase II, as the extrahepatic isoform, is the principal form in human and mouse aortic endothelial cells (ECs) and provides L‐ornithine for the synthesis of polyamines, putrescine, spermidine, and spermine (SPM), associated with cell proliferation and differentiation 6, 7. Arginase II is also inducible by hypoxia, lipopolysaccharide, and tumor necrosis factor‐α,8, 9, 10 and increased arginase II activity in ECs has recently been extended to other disorders in animal models, including aging,11 ischemic reperfusion,12, 13 hypertension,14, 15 balloon injury,16 and atherosclerosis 2.…”

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confidence: 99%

Arginase II Contributes to the Ca ²⁺ /CaMKII/eNOS Axis by Regulating Ca ²⁺ Concentration Between the Cytosol and Mitochondria in a p32‐Dependent Manner

Koo

Hwang

et al. 2018

JAHA

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BackgroundArginase II activity contributes to reciprocal regulation of endothelial nitric oxide synthase (eNOS). We tested the hypotheses that arginase II activity participates in the regulation of Ca2+/Ca2+/calmodulin‐dependent kinase II/eNOS activation, and this process is dependent on mitochondrial p32.Methods and ResultsDownregulation of arginase II increased the concentration of cytosolic Ca2+ ([Ca2+]c) and decreased mitochondrial Ca2+ ([Ca2+]m) in microscopic and fluorescence‐activated cell sorting analyses, resulting in augmented eNOS Ser1177 phosphorylation and decreased eNOS Thr495 phosphorylation through Ca2+/Ca2+/calmodulin‐dependent kinase II. These changes were observed in human umbilical vein endothelial cells treated with small interfering RNA against p32 (sip32). Using matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry, fluorescence immunoassay, and ion chromatography, inhibition of arginase II reduced the amount of spermine, a binding molecule, and the release of Ca2+ from p32. In addition, arginase II gene knockdown using small interfering RNA and knockout arginase II‐null mice resulted in reduced p32 protein level. In the aortas of wild‐type mice, small interfering RNA against p32 induced eNOS Ser1177 phosphorylation and enhanced NO‐dependent vasorelaxation. Arginase activity, p32 protein expression, spermine amount, and [Ca2+]m were increased in the aortas from apolipoprotein E (ApoE−/−) mice fed a high‐cholesterol diet, and intravenous administration of small interfering RNA against p32 restored Ca2+/Ca2+/calmodulin‐dependent kinase II‐dependent eNOS Ser1177 phosphorylation and improved endothelial dysfunction. The effects of arginase II downregulation were not associated with elevated NO production when tested in aortic endothelia from eNOS knockout mice.ConclusionsThese data demonstrate a novel function of arginase II in regulation of Ca2+‐dependent eNOS phosphorylation. This novel mechanism drives arginase activation, mitochondrial dysfunction, endothelial dysfunction, and atherogenesis.

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“…Recently, Ignarro and coworkers (5,6) showed that nitric oxide (NO) is capable of inhibiting the proliferation of rat aortic smooth muscle cells in a cGMP-independent pathway. The cytostatic action of NO was attributed to its inhibitory effect on ornithine decarboxylase, an enzyme that generates spermine, spermidine, and putrescine, which are required for cell proliferation.…”

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confidence: 99%

Reversal to cisplatin sensitivity in recurrent human ovarian cancer cells by NCX-4016, a nitro derivative of aspirin

Bratasz¹,

Weir

Parinandi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Ovarian cancer is a gynecological malignancy that is commonly treated by cytoreductive surgery followed by cisplatin treatment. However, the cisplatin treatment, although successful initially, is not effective in the treatment of the recurrent disease that invariably surfaces within a few months of the initial treatment. The refractory behavior is attributed to the increased levels of cellular thiols apparently caused by the cisplatin treatment. This observation prompted us to choose a cytotoxic drug whose activity is potentiated by cellular thiols with enhanced specificity toward the thiol-rich cisplatin-resistant cells. We used NCX-4016 [2-(acetyloxy) benzoic acid 3-(nitrooxymethyl)phenyl ester], a derivative of aspirin containing a nitro group that releases nitric oxide in a sustained fashion for several hours in cells and in vivo, and we studied its cytotoxic efficacy against human ovarian cancer cells (HOCCs). Cisplatin-sensitive and cisplatin-resistant (CR) HOCCs were treated with 100 M NCX-4016 for 6 h, and͞or 0.5 g͞ml cisplatin for 1 h and assayed for clonogenecity. NCX-4016 significantly reduced the surviving fractions of cisplatin-sensitive (63 ؎ 6%) and CR (70 ؎ 10%) HOCCs. NCX-4016 also caused a 50% reduction in the levels of cellular glutathione in CR HOCCs. Treatment of cells with NCX-4016 followed by cisplatin showed a significantly greater extent of toxicity when compared with treatment of cells with NCX-4016 or cisplatin alone. In conclusion, this study showed that NCX-4016 is a potential inhibitor of the proliferation of CR HOCCs and thus might specifically kill cisplatin-refractory cancer cells in patients with recurrent ovarian cancer.cisplatin resistance ͉ glutathione ͉ nitric oxide ͉ cytotoxicity ͉ nonsteroidal antiinflammatory drug O varian cancer is the second most commonly diagnosed gynecological malignancy and the fourth leading cause of mortality among women in the United States (1). The high mortality rate is attributed to the lack of early diagnosis of the malignancy and difficulties associated with treatment. The standard treatment includes cytoreductive surgery followed by the administration of chemotherapeutic agents. Platinum-based compounds (e.g., cisplatin and carboplatin) in combination with taxanes (e.g., taxol or paclitaxel), anthracyclines (e.g., doxorubicin), or alkylating agents (e.g., melphalan) are administered to treat the advanced-stage disease (2). However, the overall clinical response with such treatments is only 40-60%. The primary factor that limits the success of chemotherapy in ovarian cancer is the acquired drug resistance in the tumor cell population. Administration of cisplatin results in the development of drug resistance in the cancer cells. Postulated mechanisms of drug resistance include decreased intracellular accumulation of the drug, increased levels of thiols, which inactivate the platinum compound, and the enhancement of DNA repair (3). Even a slight increase in the cisplatin resistance of the tumor may pose a clinically important problem requiring ...

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Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation

Abstract: This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on April 27, 1999.The objective of this study was to elucidate the mechanisms by which nitric oxide (NO) inhibits rat aortic smooth muscle cell (

Cited by 309 publications

References 30 publications

Nitric Oxide Down-regulates Polo-like Kinase 1 through a Proximal Promoter Cell Cycle Gene Homology Region

Nitric Oxide Down-regulates Polo-like Kinase 1 through a Proximal Promoter Cell Cycle Gene Homology Region

Arginase II Contributes to the Ca ²⁺ /CaMKII/eNOS Axis by Regulating Ca ²⁺ Concentration Between the Cytosol and Mitochondria in a p32‐Dependent Manner

Reversal to cisplatin sensitivity in recurrent human ovarian cancer cells by NCX-4016, a nitro derivative of aspirin

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Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation

Abstract: This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on April 27, 1999.The objective of this study was to elucidate the mechanisms by which nitric oxide (NO) inhibits rat aortic smooth muscle cell (

Cited by 309 publications

References 30 publications

Nitric Oxide Down-regulates Polo-like Kinase 1 through a Proximal Promoter Cell Cycle Gene Homology Region

Nitric Oxide Down-regulates Polo-like Kinase 1 through a Proximal Promoter Cell Cycle Gene Homology Region

Arginase II Contributes to the Ca 2+ /CaMKII/eNOS Axis by Regulating Ca 2+ Concentration Between the Cytosol and Mitochondria in a p32‐Dependent Manner

Reversal to cisplatin sensitivity in recurrent human ovarian cancer cells by NCX-4016, a nitro derivative of aspirin

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Arginase II Contributes to the Ca ²⁺ /CaMKII/eNOS Axis by Regulating Ca ²⁺ Concentration Between the Cytosol and Mitochondria in a p32‐Dependent Manner