COX-2 is involved in vascular oxidative stress and endothelial dysfunction of renal interlobar arteries from obese Zucker rats |
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| Institution: | 1. Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid 28040, Spain;2. Departamento de Anatomía and Anatomía Patológica Comparadas, Facultad de Veterinaria, Universidad Complutense, Madrid 28040, Spain;1. Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA;2. Center for Neurosciences Initiative, Auburn University, Auburn, AL, USA;3. Center for Neuroinflammation, Georgia State University, Atlanta, GA, USA;1. Department of Histology and Embryology, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia;2. Department of Neurology, Louis Pasteur University Hospital, Kosice, Slovakia;3. 1st Department of Internal Medicine, Faculty of Medicine, Comenius University and University Hospital, Bratislava, Slovakia;4. Department of Thoracic Surgery, Faculty of Medicine and Dentistry, Medical University of Silesia, Katowice, Poland;5. University of Oviedo, Central University Hospital of Asturias (HUCA), Oviedo, Spain;6. Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic;1. Division of Cardiology, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden;2. Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan;3. RWTH-Aachen, Institute for Molecular Cardiovascular Research, Aachen, Germany;4. Department of Physiology, Pharmacology & Neuroscience, Center for Cardiovascular and Respiratory Sciences, Clinical and Translational Science Institute, West Virginia University, Morgantown, WV, United States;5. Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands;1. Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands;2. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands;3. Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Physiology, Monash University, Melbourne, Australia;4. Department of Hospital Pharmacy, Erasmus MC University Medical Center, Rotterdam, the Netherlands |
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| Abstract: | Obesity is related to vascular dysfunction through inflammation and oxidative stress and it has been identified as a risk factor for chronic renal disease. In the present study, we assessed the specific relationships among reactive oxygen species (ROS), cyclooxygenase 2 (COX-2), and endothelial dysfunction in renal interlobar arteries from a genetic model of obesity/insulin resistance, the obese Zucker rats (OZR). Relaxations to acetylcholine (ACh) were significantly reduced in renal arteries from OZR compared to their counterpart, the lean Zucker rat (LZR), suggesting endothelial dysfunction. Blockade of COX with indomethacin and with the selective blocker of COX-2 restored the relaxations to ACh in obese rats. Selective blockade of the TXA2/PGH2 (TP) receptor enhanced ACh relaxations only in OZR, while inhibition of the prostacyclin (PGI2) receptor (IP) enhanced basal tone and inhibited ACh vasodilator responses only in LZR. Basal production of superoxide was increased in arteries of OZR and involved NADPH and xanthine oxidase activation and NOS uncoupling. Under conditions of NOS blockade, ACh induced vasoconstriction and increased ROS generation that were augmented in arteries from OZR and blunted by COX-2 inhibition and by the ROS scavenger tempol. Hydrogen peroxide (H2O2) evoked both endothelium- and vascular smooth muscle (VSM)-dependent contractions, as well as ROS generation that was reduced by COX-2 inhibition. In addition, COX-2 expression was enhanced in both VSM and endothelium of renal arteries from OZR. These results suggest that increased COX-2-dependent vasoconstriction contributes to renal endothelial dysfunction through enhanced (ROS) generation in obesity. COX-2 activity is in turn upregulated by ROS. |
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| Keywords: | Obesity COX-2 Renal arteries Endothelial dysfunction Oxidative stress |
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