PMID- 31100477 OWN - NLM STAT- MEDLINE DCOM- 20200615 LR - 20211204 IS - 1873-4596 (Electronic) IS - 0891-5849 (Linking) VI - 139 DP - 2019 Aug 1 TI - Caloric restriction induces H(2)O(2) formation as a trigger of AMPK-eNOS-NO pathway in obese rats: Role for CAMKII. PG - 35-45 LID - S0891-5849(19)30599-4 [pii] LID - 10.1016/j.freeradbiomed.2019.05.016 [doi] AB - Caloric restriction (CR) improves endothelial function through the upregulation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS). Moreover, hydrogen peroxide (H(2)O(2)) is upregulated in yeast subjected to CR. Our aim was to assess if mild short-term CR increases vascular H(2)O(2) formation as a link with AMPK and eNOS activation. Twelve-week old Zucker obese (fa/fa) and control Zucker lean male rats were fed a standard chow either ad libitum (AL, n=10) or with a 20% CR (CR, n=10) for two weeks. CR significantly improved relaxation to ACh in fa/fa rats because of an enhanced endogenous production of H(2)O(2) in aortic rings (H(2)O(2) levels (fa/faAL)=0.5 +/- 0.05 nmol/mg vs. H(2)O(2) levels (fa/faCR)=0.76 +/- 0.07 nmol/mg protein; p<0.05). Expression of mitochondrial superoxide dismutase (Mn-SOD) and total SOD activity were increased in aorta from fa/fa animals after CR. In cultured aortic endothelial cells, serum deprivation or 2-deoxy-d-glucose induced a significant increase in: i) superoxide anion and H(2)O(2) levels, ii) p-AMPK/AMPK and p-eNOS/eNOS expression and iii) nitric oxide levels. This effect was reduced by catalase and strongly inhibited by Ca(2+)/calmodulin-dependent kinase II (CamkII) silencing. In conclusion, we propose that mild short-term CR might be a trigger of mechanisms aimed at protecting the vascular wall by the increase of H(2)O(2), which then activates AMPK and nitric oxide release, thus improving endothelium-dependent relaxation. In addition, we demonstrate that CAMKII plays a key role in mediating CR-induced AMPK activation through H(2)O(2) increase. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - Garcia-Prieto, Concha F AU - Garcia-Prieto CF AD - Departamento de Ciencias Farmaceuticas y de La Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28925, Madrid, Spain. FAU - Gil-Ortega, Marta AU - Gil-Ortega M AD - Departamento de Ciencias Farmaceuticas y de La Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28925, Madrid, Spain. FAU - Plaza, Adrian AU - Plaza A AD - Departamento de Ciencias Farmaceuticas y de La Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28925, Madrid, Spain. FAU - Manzano-Lista, F J AU - Manzano-Lista FJ AD - Instituto Pluridisciplinar and Departamento de Farmacologia, Facultad de Farmacia, Universidad Complutense, Madrid, Spain. FAU - Gonzalez-Blazquez, Raquel AU - Gonzalez-Blazquez R AD - Departamento de Ciencias Farmaceuticas y de La Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28925, Madrid, Spain. FAU - Alcala, Martin AU - Alcala M AD - Departamento de Quimica y Bioquimica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28925, Madrid, Spain. FAU - Rodriguez-Rodriguez, Pilar AU - Rodriguez-Rodriguez P AD - Departamento de Fisiologia, Facultad de Medicina, Universidad Autonoma, Madrid, Spain. FAU - Viana, Marta AU - Viana M AD - Departamento de Quimica y Bioquimica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28925, Madrid, Spain. FAU - Aranguez, Isabel AU - Aranguez I AD - Instituto Pluridisciplinar and Departamento de Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad Complutense, Madrid, Spain. FAU - Gollasch, Maik AU - Gollasch M AD - Experimental and Clinical Research Center, Charite - University Medicine Berlin and the Max Delbruck Center for Molecular Medicine Berlin, Germany. FAU - Somoza, Beatriz AU - Somoza B AD - Departamento de Ciencias Farmaceuticas y de La Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28925, Madrid, Spain. FAU - Fernandez-Alfonso, Maria S AU - Fernandez-Alfonso MS AD - Instituto Pluridisciplinar and Departamento de Farmacologia, Facultad de Farmacia, Universidad Complutense, Madrid, Spain. Electronic address: marisolf@ucm.es. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190515 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 11062-77-4 (Superoxides) RN - 31C4KY9ESH (Nitric Oxide) RN - 9G2MP84A8W (Deoxyglucose) RN - BBX060AN9V (Hydrogen Peroxide) RN - EC 1.11.1.6 (Catalase) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) RN - EC 1.14.13.39 (Nos3 protein, rat) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 2.7.11.31 (Prkaa1 protein, rat) SB - IM MH - AMP-Activated Protein Kinases/*genetics/metabolism MH - Animals MH - Aorta, Thoracic/metabolism/pathology MH - Calcium-Calmodulin-Dependent Protein Kinase Type 2/*genetics/metabolism MH - *Caloric Restriction MH - Catalase/genetics/metabolism MH - Deoxyglucose/pharmacology MH - Endothelial Cells/cytology/drug effects/metabolism MH - Gene Expression Regulation MH - Hydrogen Peroxide/*metabolism MH - Male MH - Nitric Oxide/metabolism MH - Nitric Oxide Synthase Type III/*genetics/metabolism MH - Obesity/*genetics/metabolism/pathology MH - Rats MH - Rats, Zucker MH - Signal Transduction MH - Superoxide Dismutase/genetics/metabolism MH - Superoxides/metabolism MH - Vasodilation OTO - NOTNLM OT - AMPK OT - Caloric restriction OT - Endothelial function OT - H(2)O(2) OT - Obesity EDAT- 2019/05/18 06:00 MHDA- 2020/06/17 06:00 CRDT- 2019/05/18 06:00 PHST- 2019/04/11 00:00 [received] PHST- 2019/05/13 00:00 [revised] PHST- 2019/05/13 00:00 [accepted] PHST- 2019/05/18 06:00 [pubmed] PHST- 2020/06/17 06:00 [medline] PHST- 2019/05/18 06:00 [entrez] AID - S0891-5849(19)30599-4 [pii] AID - 10.1016/j.freeradbiomed.2019.05.016 [doi] PST - ppublish SO - Free Radic Biol Med. 2019 Aug 1;139:35-45. doi: 10.1016/j.freeradbiomed.2019.05.016. Epub 2019 May 15.