Cyclooxygenase-2 Inhibition Limits Angiotensin II-Induced DNA Oxidation and Protein Nitration in Humans

Abstract

Compared to other cyclooxygenase-2 inhibitors, celecoxib is associated with a lower cardiovascular risk, though the mechanism remains unclear. Angiotensin II is an important mediator of oxidative stress in the pathophysiology of vascular disease. Cyclooxygenase-2 may modify the effects of angiotensin II though this has never been studied in humans. The purpose of the study was to test the effects of selective cyclooxygenase-2 inhibition on plasma measures of oxidative stress, the vasoconstrictor endothelin-1, and nitric oxide metabolites, both at baseline and in respose to Angiotensin II challenge in healthy humans. Measures of 8-hydroxydeoxyguanosine, advanced oxidation protein products, nitrotyrosine, endothelin-1, and nitric oxide metabolites were assessed from plasma samples drawn at baseline and in response to graded angiotensin II infusion (3 ng/kg/min × 30 min, 6 ng/kg/min × 30 min) before and after 14 days of cyclooxygenase-2 inhibition in 14 healthy subjects (eight male, six female) in high salt balance, a state of maximal renin angiotensin system suppression. Angiotensin II infusion significantly increased plasma oxidative stress compared to baseline (8-hydroxydeoxyguanosine; +17%; advanced oxidation protein products; +16%), nitrotyrosine (+76%). Furthermore, levels of endothelin-1 levels were significantly increased (+115%) and nitric oxide metabolites were significantly decreased (−20%). Cycloxygenase-2 inhibition significantly limited the increase in 8-hydroxydeoxyguanosine, nitrotyrosine and the decrease in nitric oxide metabolites induced by angiotensin II infusion, though no changes in advanced oxidation protein products and endothelin-1 concentrations were observed. Cyclooxygenase-2 inhibition with celecoxib partially limited the angiotensin II-mediated increases in markers of oxidative stress in humans, offering a potential physiological pathway for the improved cardiovascular risk profile of this drug.

Application of Zebrafish Model in the Suppression of Drug-Induced Cardiac Hypertrophy by Traditional Indian Medicine Yogendra Ras

“…Cyclooxygenases (COX) and nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidases/NOX) represent the primary group of enzymes involved in the generation of ROS. Overexpression of COX-2 has been associated with angiotensin-II induced oxidative stress signaling pathways and CH [47]. In the present study, co-exposure of the H9C2 cells with YDR and ISP led to an inhibition in the over-expression of COX-2 mRNA triggered by ISP alone.…”

Melatonin, Its Metabolites and Their Interference with Reactive Nitrogen Compounds

“…Moreover, the appearance of nitrated proteins can be regarded as a sign of severe stress by combined actions of RNS and ROS, as they occur when peroxynitrite is protonated or forms CO 2 adducts, followed by cleavage into oxidizing radicals and • NO 2 . This is observed in various different pathologies [ 129 , 130 , 131 , 132 , 133 , 134 , 135 ], such as cardiovascular [ 136 , 137 , 138 , 139 ] and neurodegenerative diseases [ 140 , 141 , 142 , 143 , 144 , 145 ], but also under conditions of ischemia/reperfusion [ 146 , 147 , 148 , 149 , 150 , 151 , 152 ]. In addition, mutagenic and carcinogenic effects occur, when DNA is hit by ROS and RNS, especially peroxynitrite: DNA bases are modified by RNS that cause nitration (e.g., formation of 8-nitroguanine) [ 153 , 154 , 155 , 156 , 157 ], deamination (e.g., xanthine) [ 85 , 158 ] or both (e.g., 8-nitroxanthine) [ 159 ].…”

Contribution of cyclooxygenase-2 overexpression to enhancement in tonically active glutamatergic inputs to the rostral ventrolateral medulla in hypertension

“…It has been reported that the brain Ang II is increased in patients with hypertension [50]. Ang II was also found to be involved in the regulation of COX2 function, while COX2 inhibition limits the effects of Ang II in humans [51,52]. Hence, we supposed that the function of COX2 and metabolism of PGE 2 are likely to be disturbed in human hypertension.…”