Maha Coucha1, Mohammed Abdelsaid2, Weiguo Li2, Maribeth H Johnson3, Laszlo Orfi4, Azza B El-Remessy5, Susan C Fagan6, Adviye Ergul7. 1. Charlie Norwood VA Medical Center, Augusta University, United States; Departments of Physiology, Augusta University, United States; Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, United States. 2. Charlie Norwood VA Medical Center, Augusta University, United States; Departments of Physiology, Augusta University, United States. 3. Departments of Biostatistics, Augusta University, United States. 4. Vichem Chemie, Ltd., Budapest, Hungary. 5. Charlie Norwood VA Medical Center, Augusta University, United States; Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, United States. 6. Charlie Norwood VA Medical Center, Augusta University, United States; Departments of Neurology, Augusta University, United States; Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, United States. 7. Charlie Norwood VA Medical Center, Augusta University, United States; Departments of Physiology, Augusta University, United States; Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, United States. Electronic address: aergul@augusta.edu.
Abstract
UNLABELLED: Ischemia/reperfusion and the resulting oxidative/nitrative stress impair cerebral myogenic tone via actin depolymerization. While it is known that NADPH oxidase (Nox) family is a major source of vascular oxidative stress; the extent and mechanisms by which Nox activation contributes to actin depolymerization, and equally important, the relative role of Nox isoforms in this response is not clear. AIM: To determine the role of Nox4 in hypoxia-mediated actin depolymerization and myogenic-tone impairment in cerebral vascular smooth muscle. MAIN METHODS: Control and Nox4 deficient (siRNA knock-down) human brain vascular smooth muscle cells (HBVSMC) were exposed to 30-min hypoxia/45-min reoxygenation. Nox2, Nox4, inducible and neuronal nitric oxide synthase (iNOS and nNOS) and nitrotyrosine levels as well as F:G actin were determined. Myogenic-tone was measured using pressurized arteriography in middle cerebral artery isolated from rats subjected to sham, 30-min ischemia/45-min reperfusion or ex-vivo oxygen glucose deprivation in the presence and absence of Nox inhibitors. RESULTS: Nox4 and iNOS expression were significantly upregulated following hypoxia or ischemia/reperfusion. Hypoxia augmented nitrotyrosine levels while reducing F actin. These effects were nullified by inhibiting nitration with epicatechin or pharmacological or molecular inhibition of Nox4. Ischemia/reperfusion impaired myogenic-tone, which was restored by the selective inhibition of Nox4. CONCLUSION: Nox4 activation in VSMCs contributes to actin depolymerization after hypoxia, which could be the underlying mechanism for myogenic-tone impairment following ischemia/reperfusion. Published by Elsevier Inc.
UNLABELLED: Ischemia/reperfusion and the resulting oxidative/nitrative stress impair cerebral myogenic tone via actin depolymerization. While it is known that NADPH oxidase (Nox) family is a major source of vascular oxidative stress; the extent and mechanisms by which Nox activation contributes to actin depolymerization, and equally important, the relative role of Nox isoforms in this response is not clear. AIM: To determine the role of Nox4 in hypoxia-mediated actin depolymerization and myogenic-tone impairment in cerebral vascular smooth muscle. MAIN METHODS: Control and Nox4 deficient (siRNA knock-down) human brain vascular smooth muscle cells (HBVSMC) were exposed to 30-min hypoxia/45-min reoxygenation. Nox2, Nox4, inducible and neuronal nitric oxide synthase (iNOS and nNOS) and nitrotyrosine levels as well as F:G actin were determined. Myogenic-tone was measured using pressurized arteriography in middle cerebral artery isolated from rats subjected to sham, 30-min ischemia/45-min reperfusion or ex-vivo oxygenglucose deprivation in the presence and absence of Nox inhibitors. RESULTS:Nox4 and iNOS expression were significantly upregulated following hypoxia or ischemia/reperfusion. Hypoxia augmented nitrotyrosine levels while reducing F actin. These effects were nullified by inhibiting nitration with epicatechin or pharmacological or molecular inhibition of Nox4. Ischemia/reperfusion impaired myogenic-tone, which was restored by the selective inhibition of Nox4. CONCLUSION:Nox4 activation in VSMCs contributes to actin depolymerization after hypoxia, which could be the underlying mechanism for myogenic-tone impairment following ischemia/reperfusion. Published by Elsevier Inc.
Authors: Mark D Stevenson; Chandrika Canugovi; Aleksandr E Vendrov; Takayuki Hayami; Dawn E Bowles; Karl-Heinz Krause; Nageswara R Madamanchi; Marschall S Runge Journal: Antioxid Redox Signal Date: 2018-12-28 Impact factor: 8.401