Single Perivascular Delivery of Mitomycin C Stimulates p21 Expression and Inhibits Neointima Formation in Rat Arteries

Granada, Juan F.; Ensenat, Diana; Keswani, Amit N.; Kałuża, Grzegorz L.; Raizner, Albert E.; Liu, Xiaoming; Peyton, Kelly J.; Azam, Muhammad; Wang, Hong; Durante, William

doi:10.1161/01.atv.0000184779.01822.9d

Cited by 21 publications

(26 citation statements)

References 41 publications

(40 reference statements)

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“…In addition to causing cell death, MMC has a potent antiproliferative effect (Granada et al, 2005). Therefore, we also used a colony formation assay to compare the effect of MMC on the proliferative capability in the cells expressing wild-type human POR or its variants.…”

Section: Resultsmentioning

confidence: 99%

Genetic Variation of Human Cytochrome P450 Reductase as a Potential Biomarker for Mitomycin C-Induced Cytotoxicity

Wang¹,

Han²,

He³

et al. 2006

Drug Metab Dispos

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ABSTRACT:The importance of genetic variation in clinical response to various drugs is now well recognized. Identification of genetic biomarkers that can predict efficacy and toxicity of chemotherapeutic drugs in cancer patients holds great promise in treatment improvement and cost reduction. Mitomycin C (MMC) is a common anticancer drug used for the treatment of numerous types of tumors. Metabolismmediated activation, by either one-electron or two-electron reduction, plays a critical role in the chemotherapeutic action of MMC. NADPH-cytochrome P450 (oxido)reductase (POR) is a major enzyme responsible for MMC activation through the one-electron reductive pathway, which leads to the production of semiquinone anion radicals and subsequent DNA damage in the cells. Recently, a total of six naturally occurring human POR variants with single amino acid changes (Y181D, A287P, R457H, V492E, C569Y, and V608F) have been identified. Although the catalytic efficiency of these variants in reduction of cytochrome c was reported to be altered, their capability in activating MMC, a direct substrate of POR, has not been examined. In the present study, we demonstrated that except for the C569Y variant, MMC-induced toxicity assayed as cell viability and proliferative capability was significantly decreased in the Flp-In Chinese hamster ovary cells stably expressing all the other POR variants in comparison with the cells expressing wild-type human POR. Cells expressing the V608F and Y181D variants had a complete loss of the capability to activate MMC. Our finding suggests that these functional POR genetic variations may serve as a potential biomarker to predict the chemotherapeutic response to MMC.

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Section: Resultsmentioning

confidence: 99%

Genetic Variation of Human Cytochrome P450 Reductase as a Potential Biomarker for Mitomycin C-Induced Cytotoxicity

Wang¹,

Han²,

He³

et al. 2006

Drug Metab Dispos

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“…To date, supporting evidence has included the observation that overexpression of recombinant p21 Cip1 decreases VSMC proliferation and attenuates the progression of vascular proliferative diseases (21,23,24,26) and that, conversely, reduced p21 Cip1 expression leads to increased neointimal formation following arterial injury (28). This has led to the evaluation of novel treatment strategies for these diseases that are at least partially mediated through p21 Cip1 upregulation (25,56,57). Our results further extend this work and serve to reinforce the important role of p21 Cip1 in modulating vascular wound repair.…”

Section: Discussionmentioning

confidence: 99%

p21Cip1 modulates arterial wound repair through the stromal cell–derived factor-1/CXCR4 axis in mice

Olive¹,

Mellad²,

Beltran³

et al. 2008

J. Clin. Invest.

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Cyclin-dependent kinase inhibitors, including p21 Cip1 , are implicated in cell turnover and are active players in cardiovascular wound repair. Here, we show that p21 Cip1 orchestrates the complex interactions between local vascular and circulating immune cells during vascular wound repair. In response to femoral artery mechanical injury, mice with homozygous deletion of p21 Cip1 displayed accelerated proliferation of VSMCs and increased immune cell infiltration. BM transplantation experiments indicated that local p21 Cip1 plays a pivotal role in restraining excessive proliferation during vascular wound repair. Increased local vascular stromal cell-derived factor-1 (SDF-1) levels were observed after femoral artery injury in p21 +/+ and p21 -/-mice, although this was significantly greater in p21 -/-animals. In addition, disruption of SDF-1/CXCR4 signaling inhibited the proliferative response during vascular remodeling in both p21 +/+ and p21 -/-mice. We provide evidence that the JAK/STAT signaling pathway is an important regulator of vascular SDF-1 levels and that p21 Cip1 inhibits STAT3 binding to the STAT-binding site within the murine SDF-1 promoter. Collectively, these results suggest that p21 Cip1 activity is essential for the regulation of cell proliferation and inflammation after arterial injury in local vascular cells and that the SDF-1/CXCR4 signaling system is a key mediator of vascular proliferation in response to injury.

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“…Adult male Sprague-Dawley rats (Harlan) weighing 350-450 g were anesthetized with intraperitoneal sodium pentobarbital (Nembutal) (45 mg/kg; Abbott Laboratories) and supplemental inhalational isof lurane (Forane). The left carotid artery was injured in each animal as previously described (44,56,57). Briefly, a 2-French embolectomy catheter (Applied Vascular Engineering) was inserted into the common carotid artery through the external carotid branch, and injury was induced by inflation of the balloon to 5 atmospheres of pressure for 5 minutes.…”

Section: Methodsmentioning

confidence: 99%

Nitrite-generated NO circumvents dysregulated arginine/NOS signaling to protect against intimal hyperplasia in Sprague-Dawley rats

Alef¹,

Vallabhaneni²,

Carchman³

et al. 2011

J. Clin. Invest.

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Vascular disease, a significant cause of morbidity and mortality in the developed world, results from vascular injury. Following vascular injury, damaged or dysfunctional endothelial cells and activated SMCs engage in vasoproliferative remodeling and the formation of flow-limiting intimal hyperplasia (IH). We hypothesized that vascular injury results in decreased bioavailability of NO secondary to dysregulated arginine-dependent NO generation. Furthermore, we postulated that nitrite-dependent NO generation is augmented as an adaptive response to limit vascular injury/proliferation and can be harnessed for its protective effects. Here we report that sodium nitrite (intraperitoneal, inhaled, or oral) limited the development of IH in a rat model of vascular injury. Additionally, nitrite led to the generation of NO in vessels and SMCs, as well as limited SMC proliferation via p21 Waf1/Cip1 signaling. These data demonstrate that IH is associated with increased arginase-1 levels, which leads to decreased NO production and bioavailability. Vascular injury also was associated with increased levels of xanthine oxidoreductase (XOR), a known nitrite reductase. Chronic inhibition of XOR and a diet deficient in nitrate/nitrite each exacerbated vascular injury. Moreover, established IH was reversed by dietary supplementation of nitrite. The vasoprotective effects of nitrite were counteracted by inhibition of XOR. These data illustrate the importance of nitrite-generated NO as an endogenous adaptive response and as a pathway that can be harnessed for therapeutic benefit. IntroductionVascular disease contributes significantly to morbidity and mortality in the developed world (1). Current treatments for this disease process, including surgical bypass and percutaneous interventions, are limited by the formation of intimal hyperplasia (IH) and restenosis (2). IH is an exaggerated healing process initiated by injury and characterized by platelet aggregation, leukocyte chemotaxis, extracellular matrix changes, endothelial cell apoptosis, and vascular SMC proliferation and migration (3). Investigations into vascular biology have led to the association of vascular pathology with decreased bioavailability of NO. NO is endogenously formed in the vascular endothelium by NOS using l-arginine as a substrate (4). The decreased bioavailability may occur secondary to increased consumption of NO by reactive oxygen species within the injured vessel wall or impaired synthesis of NO, possibly via decreased endothelial NO synthase, eNOS uncoupling, or dysregulation of l-arginine metabolism.l-Arginine is an important substrate for both NOS and arginase-1 enzymes, and increased arginase activity can deplete substrate availability for NO production. Interestingly, arginase-1 produces l-ornithine and activates the ornithine decarboxylase

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Single Perivascular Delivery of Mitomycin C Stimulates p21 Expression and Inhibits Neointima Formation in Rat Arteries

Cited by 21 publications

References 41 publications

Genetic Variation of Human Cytochrome P450 Reductase as a Potential Biomarker for Mitomycin C-Induced Cytotoxicity

Genetic Variation of Human Cytochrome P450 Reductase as a Potential Biomarker for Mitomycin C-Induced Cytotoxicity

p21Cip1 modulates arterial wound repair through the stromal cell–derived factor-1/CXCR4 axis in mice

Nitrite-generated NO circumvents dysregulated arginine/NOS signaling to protect against intimal hyperplasia in Sprague-Dawley rats

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