Diet-Induced Obesity Impairs Endothelium-Derived Hyperpolarization via Altered Potassium Channel Signaling Mechanisms
dc.contributor.author | Haddock, Rebecca | |
dc.contributor.author | Grayson, T. Hilton | |
dc.contributor.author | Morris, Margaret J. | |
dc.contributor.author | Howitt, Lauren | |
dc.contributor.author | Chadha, Preet S | |
dc.contributor.author | Sandow, Shaun L. | |
dc.date.accessioned | 2015-11-30T03:28:15Z | |
dc.date.available | 2015-11-30T03:28:15Z | |
dc.date.issued | 2011-01-21 | |
dc.date.updated | 2015-12-10T10:29:37Z | |
dc.description.abstract | BACKGROUND The vascular endothelium plays a critical role in the control of blood flow. Altered endothelium-mediated vasodilator and vasoconstrictor mechanisms underlie key aspects of cardiovascular disease, including those in obesity. Whilst the mechanism of nitric oxide (NO)-mediated vasodilation has been extensively studied in obesity, little is known about the impact of obesity on vasodilation to the endothelium-derived hyperpolarization (EDH) mechanism; which predominates in smaller resistance vessels and is characterized in this study. METHODOLOGY/PRINCIPAL FINDINGS Membrane potential, vessel diameter and luminal pressure were recorded in 4(th) order mesenteric arteries with pressure-induced myogenic tone, in control and diet-induced obese rats. Obesity, reflecting that of human dietary etiology, was induced with a cafeteria-style diet (∼30 kJ, fat) over 16-20 weeks. Age and sexed matched controls received standard chow (∼12 kJ, fat). Channel protein distribution, expression and vessel morphology were determined using immunohistochemistry, Western blotting and ultrastructural techniques. In control and obese rat vessels, acetylcholine-mediated EDH was abolished by small and intermediate conductance calcium-activated potassium channel (SK(Ca)/IK(Ca)) inhibition; with such activity being impaired in obesity. SK(Ca)-IK(Ca) activation with cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) and 1-ethyl-2-benzimidazolinone (1-EBIO), respectively, hyperpolarized and relaxed vessels from control and obese rats. IK(Ca)-mediated EDH contribution was increased in obesity, and associated with altered IK(Ca) distribution and elevated expression. In contrast, the SK(Ca)-dependent-EDH component was reduced in obesity. Inward-rectifying potassium channel (K(ir)) and Na(+)/K(+)-ATPase inhibition by barium/ouabain, respectively, attenuated and abolished EDH in arteries from control and obese rats, respectively; reflecting differential K(ir) expression and distribution. Although changes in medial properties occurred, obesity had no effect on myoendothelial gap junction density. CONCLUSION/SIGNIFICANCE In obese rats, vasodilation to EDH is impaired due to changes in the underlying potassium channel signaling mechanisms. Whilst myoendothelial gap junction density is unchanged in arteries of obese compared to control, increased IK(Ca) and Na(+)/K(+)-ATPase, and decreased K(ir) underlie changes in the EDH mechanism. | |
dc.description.sponsorship | This work was supported by grants from the National Health and Medical Research Council of Australia [ID 466009 to REH, ID 401112 SLS and ID 455243 to SLS and MJM]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. | en_AU |
dc.identifier.issn | 1932-6203 | en_AU |
dc.identifier.uri | http://hdl.handle.net/1885/16911 | |
dc.publisher | Public Library of Science | |
dc.relation | http://purl.org/au-research/grants/nhmrc/466009 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/401112 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/455243 | |
dc.rights | © 2011 Haddock et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | |
dc.source | PLoS ONE | |
dc.source.uri | http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0016423 | en_AU |
dc.subject | animals | |
dc.subject | diet | |
dc.subject | endothelium, vascular | |
dc.subject | gap junctions | |
dc.subject | obesity | |
dc.subject | potassium channels | |
dc.subject | rats | |
dc.subject | signal transduction | |
dc.subject | tissue distribution | |
dc.subject | vasodilation | |
dc.subject | membrane potentials | |
dc.title | Diet-Induced Obesity Impairs Endothelium-Derived Hyperpolarization via Altered Potassium Channel Signaling Mechanisms | |
dc.type | Journal article | |
local.bibliographicCitation.issue | 1 | en_AU |
local.bibliographicCitation.lastpage | 13 | |
local.bibliographicCitation.startpage | e16423 | en_AU |
local.contributor.affiliation | Haddock, Rebecca, College of Medicine, Biology and Environment, CMBE John Curtin School of Medical Research, Eccles Institute of Neuroscience, The Australian National University | en_AU |
local.contributor.affiliation | Grayson , T Hilton, University of New South Wales, Australia | en_AU |
local.contributor.affiliation | Morris, MJ, University of New South Wales, Australia | en_AU |
local.contributor.affiliation | Howitt, Lauren, College of Medicine, Biology and Environment, CMBE John Curtin School of Medical Research, Eccles Institute of Neuroscience, The Australian National University | en_AU |
local.contributor.affiliation | Chadha, Preet S, University of New South Wales, Australia | en_AU |
local.contributor.affiliation | Sandow, Shaun, L, University of New South Wales, Australia | en_AU |
local.contributor.authoremail | Rebecca.Haddock@anu.edu.au | en_AU |
local.contributor.authoremail | Shaun.Sandow@unsw.edu.au | en_AU |
local.contributor.authoruid | Haddock, Rebecca, u9718723 | en_AU |
local.description.notes | Imported from ARIES | en_AU |
local.identifier.absfor | 110201 | en_AU |
local.identifier.ariespublication | f2965xPUB1289 | en_AU |
local.identifier.citationvolume | 6 | en_AU |
local.identifier.doi | 10.1371/journal.pone.0016423 | en_AU |
local.identifier.essn | 1932-6203 | en_AU |
local.identifier.scopusID | 2-s2.0-79251633164 | |
local.identifier.thomsonID | 000286522300045 | |
local.identifier.uidSubmittedBy | u3488905 | en_AU |
local.publisher.url | http://journals.plos.org/ | en_AU |
local.type.status | Published Version | en_AU |
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