NSAIDs and Cardiovascular Diseases: Role of Reactive Oxygen Species

Table 3

NSAIDs induced ROS generation in different cell types.

(a)

NSAIDs; Nonselective/semiselective	Sources of ROS generation	Cells/models/animals studied	Outcomes	References
Diclofenac, indomethacin, ketoprofen	Mitochondrial respiration	Saccharomyces cerevisiae Yeast cells BY4741 and mitochondrial DNA deletion (rho^0) strains	These NSAIDs target mitochondria to induce cell toxicity	[95]
Ibuprofen and naproxen			These NSAIDS induce toxicity independent of mitochondrial respiration	[95]
Indomethacin, sodium diclofenac, flurbiprofen, zaltoprofen, and mofezolac	ND	Human gastric epithelial cell line AGS	All NSAIDs except mofezolac increased apoptotic DNA fragmentation and expression of COX-2 mRNA. DNA fragmentation induced by indomethacin or flurbiprofen was reduced by antioxidants. Indomethacin at 1 mM was a potent inducer of ROS generation in the cells	[79]
Diclofenac and naproxen	NADPH oxidases	Spontaneous hypertensive rats	NADPH oxidase expression increased in the heart and aorta by diclofenac and naproxen. ROS levels increased due to NADPH oxidase	[114]
		Human EA.hy 926; Endothelial cells	Nox2 isoform of NADPH oxidase is increased by diclofenac	[114]
Aspirin, naproxen, and piroxicam	NADPH oxidases	Rat adipocytes	Activation of NOX 4 isoform of NADPH oxidase results in the generation of H2O2	[115]
Indomethacin	Xanthine oxidases	Human colonic adenocarcinoma cells (Caco-2 cells)	Xanthine oxidase activity increases by more than 100% 1 hour after treatment	[96]
Indomethacin	Mitochondria superoxide leakage	Rat gastric epithelial cell line RGM1	Indomethacin induced the leakage of superoxide anion in the isolated mitochondria from the gastric RGM1 cells	[93]
Indomethacin, diclofenac sodium, and aspirin	ND	Rat gastric epithelial cell line RGM1 and rat small intestinal epithelial cell line IEC6	Indomethacin, diclofenac, and aspirin in gastric RGM1 cells and small intestinal IEC6 cells increased lipid peroxidation	[93]
Sulindac, sulindac sulfide, and sulindac sulfone	ND	Pancreas carcinoma BXPC3, glioblastoma A172, colon carcinoma DLD-1, oral squamous SAS, and acute myelocytic leukemia HL60 cells	The NSAID sulindac and its metabolites sulindac sulfide and sulindac sulfone all increased ROS generation. Sulindac sulfide showed the greatest ROS generation	[80]
Indomethacin, piroxicam, and aspirin	Lipoxygenases	Gastric and intestinal mucosa in mice	Results in an overproduction of leukotrienes and products of 5-lipoxygenase activity. Increases in leukotriene and 5-lipoxygenase activity have been associated with ROS generation	[123, 124, 127]
Indomethacin	Lipoxygenases	Efferent gastric circulation of pigs	Time dependent formation of leukotriene-C4	[128]
Diclofenac	Cytochrome P450 enzymes	Saccharomyces cerevisiae yeast cells expressing the mutant P 450 BM3 M11 (capable of metabolizing diclofenac similar to humans)	Increased ROS production by ~1.5 and 1.8 times at concentrations of 30 μM and 50 μM, respectively, compared to wild type	[140]
Diclofenac, indomethacin, ketoprofen, and naproxen	Cytochrome P450 enzymes	Saccharomyces cerevisiae Yeast cells BY4741 and mitochondrial DNA deletion (rho^0) strains	NSAIDs metabolism associated with increased P450-related toxicity	[95]

(b)

NSAIDs; coxibs	Sources of ROS generation	Cells/models/animals studied	Outcomes	References
Ibuprofen, ketoprofen, and indomethacin	Cytochrome P450 enzymes	Bacillus megaterium	All the NSAIDs caused a marked increase in the total cytochrome P450 level	[142]
Aspirin, diclofenac, diflunisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, naproxen, piroxicam, sulindac, and tolmetin	Cytochrome P450 enzymes	Rat hepatocytes	Cytotoxicity of diclofenac, ketoprofen, and piroxicam was increased by cytochrome P450 causing hepatotoxicity	[138]
Diclofenac and naproxen	Endothelial nitric oxide synthase	Spontaneous hypertensive rats	Increased expression of eNOS mRNA due to the generation of H2O2 which is responsible for upregulation of eNOS at the transcriptional and post-transcriptional levels	[114]
Rofecoxib and celecoxib	NADPH oxidases	Spontaneous hypertensive rats	NADPH expression increased in the heart and aorta by rofecoxib and celecoxib	[114]
		Human EA.hy 926; Endothelial cells	Nox2 Expression increased by rofecoxib	[114]
Rofecoxib and celecoxib	Endothelial nitric oxide synthase	Spontaneous hypertensive rats	In the aorta, the coxibs did not show any eNOS mRNA expression. In the heart only rofecoxib showed a significant increase in the expression of eNOS	[114]
Etodolac	ND	Human gastric epithelial cell line AGS	Increased apoptotic DNA fragmentation and expression of COX-2 mRNA	[79]
Nimesulide	NADPH oxidases	Rat adipocytes	Activation of NOX 4 isoform of NADPH oxidase results in the generation of H2O2	[115]

^*Although other reports are available suggesting the role of NSAIDs in ROS formation, the table lists only those NSAIDs for which results show that these NSAIDs are associated with CVD or NSAIDs mentioned in the text.