Differential Expression of Genes from Nitrate-Tolerant Rat Aorta

Pi, Xinchun; Yan, Chen; Kim, Dong Soo; Chen, Jiyuan; Berk, Bradford C.

doi:10.1159/000065542

Cited by 14 publications

(6 citation statements)

References 24 publications

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“…Overall, the gene array study revealed that NTG caused substantial and broad changes in the gene expression of a number of ECM proteases and adhesion molecules (Tables 2–4). The ability of NTG to cause extensive cellular gene regulation is consistent with our previous observation [26], confirmed by others [33], that wide-spread changes in vascular gene expression occurred in rats after chronic exposure and tolerance development, to NTG in vivo .…”

Section: Discussionsupporting

confidence: 92%

Broad regulation of matrix and adhesion molecules in THP-1 human macrophages by nitroglycerin

Krishnatry¹,

Brazeau²,

Fung³

2010

Nitric Oxide

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Although nitroglycerin (NTG) is effective for the acute relief in coronary ischemic diseases, its longterm benefits in mortality and morbidity have been questioned. The possibility has been raised that NTG may increase the activity of matrix metalloproteinases (MMP), which could lead to disruption and dislodging of atherosclerotic plaques. This study examined the broad effects of acute NTG exposure on the expression and activity of genes encoding MMP-9, as well as an array of ECM and adhesion molecules in THP-1 human macrophages. Gene array studies identified that while NTG exposure (100 µM, 48 hours) did not significantly increase MMP-9 gene expression, genes encoding testican-1, integrin α-1, thrombospondin-3, fibronectin-1 and MMP-26 were significantly downregulated. On the other hand, genes encoding catenin β-1 and vascular cell adhesion molecule-1 were up-regulated. Real-time PCR studies confirmed significant down-regulation of testican-1 gene expression, but its protein expression was not significantly altered. NTG exposure, caused a significant increase in total MMP-9 protein expression (1.96-fold) and active MMP-9 (3.7-fold) concentrations. Recombinant MMP-9 was significantly activated by NTG and its dinitrate metabolites, indicating post-translation modification of this protein by organic nitrates. These results indicate that NTG exposure could broadly affect the gene expression and activity of proteases that govern the ECM cascade, thereby potentially altering atherosclerotic plaque stability.

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Section: Discussionsupporting

confidence: 92%

Broad regulation of matrix and adhesion molecules in THP-1 human macrophages by nitroglycerin

Krishnatry¹,

Brazeau²,

Fung³

2010

Nitric Oxide

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“…Our results confirmed previous observations that exposure to NTG may cause extensive changes in cellular and tissue gene regulation, as were shown for THP-1 macrophages [19], and in vascular tissues [48; 49]. However, the specific genes that were affected in the present experiment differed substantially from those observed after acute high-concentration exposure [19].…”

Section: Discussionsupporting

confidence: 92%

Nitroglycerin alters matrix remodeling proteins in THP-1 human macrophages and plasma metalloproteinase activity in rats

Krishnatry¹,

Fung²,

Brazeau³

et al. 2011

Nitric Oxide

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Several studies suggested that long-term nitrate therapy may produce negative outcomes in patient mortality and morbidity. A possible mechanism may involve nitrate-mediated activation of various extracellular matrix (ECM) proteases, particularly matrix metalloproteinase-9 (MMP-9), and adhesion molecules in human macrophages, leading to the destabilization of atherosclerotic plaques. We examined the gene and protein regulating effects on THP-1 human macrophages by repeated exposure to therapeutically relevant concentrations of nitroglycerin (NTG) and possible involvement of nuclear factor (NF)-κB signaling mechanism in mediating some of these observed effects. THP-1 human macrophages repeatedly exposed to NTG (at 10 nM, added on days 1, 4 and 7) exhibited extensive alterations in the expression of multiple genes encoding ECM proteases and adhesion molecules. These effects were dissimilar to those produced by a direct nitric oxide donor, diethylenetriamine NONOate. NTG exposure significantly up-regulated NF-κB DNA nuclear binding activity and MMP-9 protein expression, and reduced tissue inhibitor of metalloproteinase-1 (TIMP-1) expression; these effects were abrogated in the presence of the NF-κB inhibitor parthenolide (a chemical inhibitor derived from the feverfew plant). Further, we examined whether our in vitro findings (an elevated MMP-9/TIMP-1 ratio and gelatinase activity) can be translated to in vivo effects, in a rat model. Sprague-Dawley rats exposed continuously to NTG subcutaneously for 8 days via mini-osmotic pumps showed significant induction of plasma MMP-9 dimer concentrations and the expression of a complex of MMP-9 with lipocalin-2 or neutrophil gelatinase associated lipocalin (NGAL). Plasma gelatinase activity was significantly increased by NTG over the entire study period, attaining peak elevation at day 6. Plasma TIMP-1 protein was down-regulated significantly by day 2 and days 4 to 7 in the NTG-treated rats. Pharmacokinetic monitoring of NTG and its dinitrate metabolites indicated that concentrations were well within therapeutic levels observed in humans. Our studies indicate that clinically relevant concentrations of NTG not only altered ECM matrix by changing the expression of multiple genes that govern cellular integrity, affecting cellular MMP-9/TIMP-1 balance in THP-1 human macrophages possibly via NF-κB activation, but also led to systemic changes in MMP-9/ TIMP-1 expression and gelatinase activity in rats. These effects may contribute to extracellular matrix degradation and possible atherosclerotic plaque destabilization.

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“…At the top of the list are α 2 - and β-globins, which have been observed to be upregulated in rat aorta chronically treated with nitroglycerin. 22 One of the most commonly recognized features of atherosclerosis in diabetics is an upregulation of CD36 messenger ribonucleic acid (mRNA) and protein. This response by macrophages to hyperglycemia contributes to accelerated atherogenesis in diabetic patients.…”

Section: Discussionmentioning

confidence: 99%

Genomic Modeling of Atherosclerosis in Peripheral Arterial Disease and Its Variant Phenotype in Patients with Diabetes

Evans

Sileshi²,

Zakaria³

et al. 2008

Vascular

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Microarrays can be used to discover candidate genes associated with peripheral arterial disease (PAD) and develop models that predict patient clinical status. We hypothesize that multiple phenotypes of PAD with distinct patterns of gene expression exist. We histologically characterized and extracted ribonucleic acid from 31 arterial samples collected from the lower extremities of patients undergoing amputation or free fibular grafting. Analysis using the Affymetrix U133A microarray identified 335 genes with twofold or greater differences in expression between normal and diseased arteries (p< .01) and 104 genes with twofold or greater differences between diabetic and nondiabetic atherosclerotic arteries (p< .1). Many genes identified have known roles in inflammatory and lipid uptake pathways. Predictive models were developed that could predict PAD and the associated diabetic phenotype with an accuracy of 71 to 90%. Developing distinct genomic models of PAD will serve as the first step toward understanding the molecular and genetic basis of PAD and subsequent application of novel therapeutics to this condition.

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Differential Expression of Genes from Nitrate-Tolerant Rat Aorta

Cited by 14 publications

References 24 publications

Broad regulation of matrix and adhesion molecules in THP-1 human macrophages by nitroglycerin

Broad regulation of matrix and adhesion molecules in THP-1 human macrophages by nitroglycerin

Nitroglycerin alters matrix remodeling proteins in THP-1 human macrophages and plasma metalloproteinase activity in rats

Genomic Modeling of Atherosclerosis in Peripheral Arterial Disease and Its Variant Phenotype in Patients with Diabetes

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