FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3100582556> ?p ?o ?g. }

• W3100582556 endingPage "1995" @default.
• W3100582556 startingPage "1993" @default.
• W3100582556 abstract "HomeCirculationVol. 142, No. 20Lysyl Oxidase Inhibition Ablates Sexual Dimorphism of Abdominal Aortic Aneurysm Formation in Mice Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLysyl Oxidase Inhibition Ablates Sexual Dimorphism of Abdominal Aortic Aneurysm Formation in Mice Michihiro Okuyama, MD, PhD, Weihua Jiang, BS, Aida Javidan, MS, Jeff Zheying Chen, PhD, Deborah A. Howatt, BS, Lihua Yang, BS, Mika Hamaguchi, MD, Takumi Yasugi, MD, PhD, Jun Aono, MD, PhD, Roberto Irenardo Vazquez-Padron, PhD and Venkateswaran Subramanian, PhD Michihiro OkuyamaMichihiro Okuyama Saha Cardiovascular Research Center (M.O., W.J., A.J., J.Z.C., D.A.H., L.Y., V.S.), University of Kentucky, Lexington. *Dr Okuyama, W. Jiang, A. Javidan, and Dr Chen contributed equally. Search for more papers by this author , Weihua JiangWeihua Jiang Saha Cardiovascular Research Center (M.O., W.J., A.J., J.Z.C., D.A.H., L.Y., V.S.), University of Kentucky, Lexington. *Dr Okuyama, W. Jiang, A. Javidan, and Dr Chen contributed equally. Search for more papers by this author , Aida JavidanAida Javidan Saha Cardiovascular Research Center (M.O., W.J., A.J., J.Z.C., D.A.H., L.Y., V.S.), University of Kentucky, Lexington. *Dr Okuyama, W. Jiang, A. Javidan, and Dr Chen contributed equally. Search for more papers by this author , Jeff Zheying ChenJeff Zheying Chen Saha Cardiovascular Research Center (M.O., W.J., A.J., J.Z.C., D.A.H., L.Y., V.S.), University of Kentucky, Lexington. Department of Physiology (J.Z.C., V.S.), University of Kentucky, Lexington. *Dr Okuyama, W. Jiang, A. Javidan, and Dr Chen contributed equally. Search for more papers by this author , Deborah A. HowattDeborah A. Howatt Saha Cardiovascular Research Center (M.O., W.J., A.J., J.Z.C., D.A.H., L.Y., V.S.), University of Kentucky, Lexington. Search for more papers by this author , Lihua YangLihua Yang Saha Cardiovascular Research Center (M.O., W.J., A.J., J.Z.C., D.A.H., L.Y., V.S.), University of Kentucky, Lexington. Search for more papers by this author , Mika HamaguchiMika Hamaguchi Department of Cardiology, Pulmonology, Hypertension, and Nephrology (M.H., J.A.), Ehime University Graduate School of Medicine, Toon, Japan. Search for more papers by this author , Takumi YasugiTakumi Yasugi Department of Cardiovascular and Thoracic Surgery (T.Y.), Ehime University Graduate School of Medicine, Toon, Japan. Search for more papers by this author , Jun AonoJun Aono https://orcid.org/0000-0002-8324-6625 Department of Cardiology, Pulmonology, Hypertension, and Nephrology (M.H., J.A.), Ehime University Graduate School of Medicine, Toon, Japan. Search for more papers by this author , Roberto Irenardo Vazquez-PadronRoberto Irenardo Vazquez-Padron Department of Surgery, Division of Vascular Surgery, University of Miami, FL (R.I.V.-P.). Search for more papers by this author and Venkateswaran SubramanianVenkateswaran Subramanian Venkateswaran Subramanian, PhD, Saha Cardiovascular Research Center, Department of Physiology, BBSRB - Room 261, University of Kentucky, Lexington, KY 40536-0509. Email E-mail Address: [email protected] https://orcid.org/0000-0002-1183-7717 Saha Cardiovascular Research Center (M.O., W.J., A.J., J.Z.C., D.A.H., L.Y., V.S.), University of Kentucky, Lexington. Department of Physiology (J.Z.C., V.S.), University of Kentucky, Lexington. Search for more papers by this author Originally published16 Nov 2020https://doi.org/10.1161/CIRCULATIONAHA.119.044986Circulation. 2020;142:1993–1995This article is commented on by the following:Colchicine for Secondary Cardiovascular Prevention in Coronary DiseaseEditorial, see p 1901Abdominal aortic aneurysm (AAA) formation involves a complex process of aortic medial destruction through degradation of extracellular matrix proteins, elastin, and collagen. AAA exhibits sexual dimorphism because male sex is a major risk factor of AAA in both mice and humans.1 In mice, testosterone has been implicated as a major contributor to sexual dimorphism of angiotensin II (AngII)–induced AAAs.2 However, the mechanism by which testosterone drives sexual dimorphism of AAA is unknown. During aortic development, lysyl oxidase (LOX) covalently cross-links elastin and collagen to create an insoluble extracellular matrix resistant to proteolytic degradation.3 We hypothesized that testosterone-mediated suppression of LOX activity is a critical contributor to increased susceptibility of male to AAA formation. Ethics and institutional review board approvals were provided by University of Kentucky (Protocol-2011-0907) and the Ehime University (Protocol-1603002), and informed consent was received from all participants.To test this hypothesis, we first evaluated LOX protein in human male and female, nonaneurysmal and aneurysmal, abdominal aortic sections. LOX protein was significantly more abundant in the aortic media in female nonaneurysmal and aneurysmal aortic sections than in male nonaneurysmal and aneurysmal aortic sections (Figure A). Consistent with observations in humans, abdominal aortas from female C57BL/6J mice showed significantly more LOX protein in the aortic media than from male mice (Figure B). To discern whether this sexual dimorphism was functionally relevant, we examined LOX activity by measuring breakdown of fluorescent-labeled LOX substrate in aortic tissues from male and female mice infused with either saline or AngII (1000 ng·kg–1·min–1) for 7 days. Consistent with LOX protein abundance, LOX activity in female aortic tissue was ≈2.5-fold significantly higher than in male aortic tissue, and AngII infusion had no influence on LOX activity in either sex (Figure C). To explore whether sex hormones regulate aortic LOX activity, 8-week-old male and female mice were subjected to either castration (orchiectomy or ovariectomy) or sham operation. Four weeks after surgery, abdominal aortic LOX activity was measured. Orchiectomy of male mice not only significantly increased LOX activity, in comparison with sham controls, but to a level present in female mice. Ovariectomy had no influence on LOX activity in female mice in comparison with sham controls (Figure D). Furthermore, testosterone replacement by dihydrotestosterone pellet (16 µg/d subcutaneously) administration for 2 weeks significantly suppressed LOX activity in orchiectomized mice similar to sham controls (Figure E). These results suggest that androgens, not estrogens, regulate and suppress aortic LOX activity in mice.Download figureDownload PowerPointFigure. LOX is a novel target for AAA.A, Immunohistochemical staining revealed that LOX protein is more abundant in the media of female human nonaneurysmal and aneurysmal abdominal aortic sections (red indicates positive immunostaining; Abcam, ab31238; n=3, *P<0.05 AAA vs NAA; $P<0.05 female NAA vs male NAA; #P<0.05 female AAA vs male AAA; 2-way ANOVA followed by Holm-Sidak post hoc test). B, LOX protein is more abundant in aortic media of female mouse abdominal aortic sections than in male mouse abdominal aortic sections (n=3, *P<0.05 female vs male; Student t test). C, Aortic LOX activity is lower in male mice infused with either saline or AngII (1000 ng·kg–1·min–1 for 5 days) than in female mice (Abcam, ab112139; n=4, *P<0.05 female vs male; 2-way ANOVA followed by Holm-Sidak post hoc test). D, Orchiectomy (ORCH) not ovariectomy (OVX) increased aortic LOX activity in mice (n=5, *P<0.05 vs male sham; 2-way ANOVA followed by Holm-Sidak post hoc test). E, Testosterone replacement suppressed aortic LOX activity in ORCH mice (n=4–5, *P<0.05 ORCH vs sham; #ORCH+testosterone vs ORCH; 1-way ANOVA followed by Holm-Sidak pairwise multiple comparison test). F and G, LOX inhibition by BAPN (0.15 g·kg–1·d–1) accelerated 28 days infusion of AngII-induced aortic luminal dilation measured by ultrasound (Vivo 2100) in female mice as similar to male mice (n=5–25, *P<0.05 AngII+BAPN vs saline/BAPN/AngII; 2-way repeated-measures ANOVA). H though L, LOX inhibition accelerated AngII-induced AAA formation and incidence in female mice as similar to male mice (n=5–25, *P<0.05 AngII+BAPN vs saline/BAPN/AngII; 2-way ANOVA followed by Holm-Sidak post hoc test). M and N, LOX inhibition resulted in loss of medial SMCs (α-SMC actin staining; Abcam, ab5694) along with AngII-induced aortic medial elastin breakage (Verhoeff staining) equivalently in both male and female mice (n=3, *P<0.05 vs male/female saline; 2-way ANOVA followed by Holm-Sidak post hoc test). Scale bars correspond to 50 μm (×200 magnification). O through R, BAPN administration accelerated AngII-induced AAA formation in ORCH mice and testosterone replacement significantly promoted AngII+BAPN–induced AAA rupture in ORCH mice (n=9–10, #P<0.05 ORCH+testosterone vs ORCH; 1-way ANOVA and Fisher exact test). A indicates angiotensin II; AAA, abdominal aortic aneurysm; AngII, angiotensin II; A+B, AngII+BAPN; BAPN, β-aminopropionitrile; LOX, lysyl oxidase; NAA, nonaneurysmal abdominal aorta; S, saline; S+B, saline plus BAPN; SMC, smooth muscle cell; and U/S, ultrasound.Previous studies have indicated that AngII infusion promotes AAA incidence ≈80% in male hyperlipidemic mice but only ≈10% in male normolipidemic mice. Conversely, AngII infusion caused <10% AAA incidence in both hyperlipidemic and normolipidemic female mice.4 Recently, pharmacological inhibition of LOX by β-aminopropionitrile (BAPN) was shown to promote AngII-induced AAA formation (>80%) in normolipidemic male mice.5 However, the effect of LOX inhibition on sexual dimorphism of AngII-induced AAA in female mice is unknown. To test whether LOX inhibition influences sexual dimorphism of AAAs, male and female mice were infused as follows: (1) saline, (2) saline+BAPN (0.15 g·kg–1·d–1), (3) AngII (1000 ng·kg–1·min–1), and (4) AngII+BAPN. Mice were infused with either saline or AngII through osmotic minipumps for 28 days. BAPN was administered in drinking water (1 mg/mL; 0.15 g·kg–1·d–1) from day 0 to day 14.5 The development of AAA was assessed by (1) ultrasound measurement of aortic luminal dilation, (2) ex vivo measurement of external abdominal aortic width, and (3) AAA incidence defined as 50% increase in luminal dilation in comparison with baseline.AngII infusion resulted in a 25% (2 of 8) AAA incidence (Figure I–L) with no significant aortic luminal dilation and expansion in comparison with saline/BAPN groups in male but not female mice (Figure F–H). Consistent with previous publications, AngII+BAPN administration increased AAA incidence to 82% (19/23; Figure I and K) with significant luminal dilation and expansion (Figure F–H), along with 30% (7 of 23) aortic rupture in male mice. In female mice, AngII+BAPN administration showed a significant aortic luminal dilation and expansion (Figure F–H) along with a 72% AAA incidence (18 of 25; Figure J and L) and 12% (3 of 25) rupture. These results indicate that pharmacological inhibition of LOX abolishes sexual dimorphism in AngII-induced AAA formation by equally exacerbating aortic dilation and rupture in both male and female mice. Immunohistochemistry and histological analysis revealed that LOX inhibition significantly reduced medial α-smooth muscle cell actin–positive area and promoted AngII-induced medial elastin breakage equivalently in both male and female mice (Figure M and N). BAPN administration promoted AngII-induced AAA formation in orchiectomized mice similar to sham controls (Figure O and P), and testosterone replacement significantly promoted AngII+BAPN–induced AAA rupture (7 of 10) in orchiectomized mice in comparison with orchiectomized controls (0 of 10; Figure Q and R), which strongly demonstrates that maintenance of LOX activity is critical to protect the castrated mice from AAA development.To our knowledge, this study is the first report to implicate LOX in the sexual dimorphism of AAAs. Stabilization or restoration of LOX may abolish sexual dimorphism and reduce abdominal aortic dilation in males to levels similar to those in females.AcknowledgmentsWe acknowledge the skilled editorial assistance of D. L. Rateri.Sources of FundingThis study was supported by a Scientist Development Grant (14SDG18740000 to V.S.) from the American Heart Association and by the National Institutes of Health (grants P20GM103527, R01HL130086 to V.S. and R01HL133723).DisclosuresNone.Footnotes*Dr Okuyama, W. Jiang, A. Javidan, and Dr Chen contributed equally.https://www.ahajournals.org/journal/circThe data, analytic methods, and study materials will be maintained by the corresponding author and made available to other researchers on reasonable request.Venkateswaran Subramanian, PhD, Saha Cardiovascular Research Center, Department of Physiology, BBSRB - Room 261, University of Kentucky, Lexington, KY 40536-0509. Email venkat.[email protected]eduReferences1. Boese AC, Chang L, Yin KJ, Chen YE, Lee JP, Hamblin MH. Sex differences in abdominal aortic aneurysms.Am J Physiol Heart Circ Physiol. 2018; 314:H1137–H1152. doi: 10.1152/ajpheart.00519.2017CrossrefMedlineGoogle Scholar2. Henriques TA, Huang J, D’Souza SS, Daugherty A, Cassis LA. Orchidectomy, but not ovariectomy, regulates angiotensin II-induced vascular diseases in apolipoprotein E-deficient mice.Endocrinology. 2004; 145:3866–3872. doi: 10.1210/en.2003-1615CrossrefMedlineGoogle Scholar3. Rodríguez C, Martínez-González J, Raposo B, Alcudia JF, Guadall A, Badimon L. Regulation of lysyl oxidase in vascular cells: lysyl oxidase as a new player in cardiovascular diseases.Cardiovasc Res. 2008; 79:7–13. doi: 10.1093/cvr/cvn102CrossrefMedlineGoogle Scholar4. Zhang X, Thatcher SE, Rateri DL, Bruemmer D, Charnigo R, Daugherty A, Cassis LA. Transient exposure of neonatal female mice to testosterone abrogates the sexual dimorphism of abdominal aortic aneurysms.Circ Res. 2012; 110:e73–e85. doi: 10.1161/CIRCRESAHA.111.253880LinkGoogle Scholar5. Kawai T, Takayanagi T, Forrester SJ, Preston KJ, Obama T, Tsuji T, Kobayashi T, Boyer MJ, Cooper HA, Kwok HF, et al.. Vascular ADAM17 (a disintegrin and metalloproteinase domain 17) is required for angiotensin II/β-aminopropionitrile-induced abdominal aortic aneurysm.Hypertension. 2017; 70:959–963. doi: 10.1161/HYPERTENSIONAHA.117.09822LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Berman A, Romary D, Kerr K, Gorazd N, Wigand M, Patnaik S, Finol E, Cox A and Goergen C (2022) Experimental aortic aneurysm severity and growth depend on topical elastase concentration and lysyl oxidase inhibition, Scientific Reports, 10.1038/s41598-021-04089-8, 12:1, Online publication date: 1-Dec-2022. Mao X, Wang X, Jin M, Li Q, Jia J, Li M, Zhou H, Liu Z, Jin W, Zhao Y and Luo Z (2022) Critical involvement of lysyl oxidase in seizure-induced neuronal damage through ERK-Alox5-dependent ferroptosis and its therapeutic implications, Acta Pharmaceutica Sinica B, 10.1016/j.apsb.2022.04.017, Online publication date: 1-May-2022. Related articlesColchicine for Secondary Cardiovascular Prevention in Coronary DiseaseFrançois Roubille, et al. Circulation. 2020;142:1901-1904 November 17, 2020Vol 142, Issue 20 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.119.044986PMID: 33196308 Originally publishedNovember 16, 2020 Keywordsangiotensin IIaminopropionitrilesex characteristicsprotein-lysine 6-oxidaseaortic aneurysm, abdominalPDF download Advertisement" @default.
• W3100582556 created "2020-11-23" @default.
• W3100582556 creator A5005650204 @default.
• W3100582556 creator A5018416427 @default.
• W3100582556 creator A5033380392 @default.
• W3100582556 creator A5033714582 @default.
• W3100582556 creator A5034103646 @default.
• W3100582556 creator A5041709209 @default.
• W3100582556 creator A5042531886 @default.
• W3100582556 creator A5047640192 @default.
• W3100582556 creator A5060379321 @default.
• W3100582556 creator A5084686245 @default.
• W3100582556 creator A5086015666 @default.
• W3100582556 date "2020-11-17" @default.
• W3100582556 modified "2023-09-25" @default.
• W3100582556 title "Lysyl Oxidase Inhibition Ablates Sexual Dimorphism of Abdominal Aortic Aneurysm Formation in Mice" @default.
• W3100582556 cites W2052522179 @default.
• W3100582556 cites W2109769352 @default.
• W3100582556 cites W2143059560 @default.
• W3100582556 cites W2758193218 @default.
• W3100582556 cites W2782691119 @default.
• W3100582556 doi "https://doi.org/10.1161/circulationaha.119.044986" @default.
• W3100582556 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7678818" @default.
• W3100582556 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33196308" @default.
• W3100582556 hasPublicationYear "2020" @default.
• W3100582556 type Work @default.
• W3100582556 sameAs 3100582556 @default.
• W3100582556 citedByCount "12" @default.
• W3100582556 countsByYear W31005825562022 @default.
• W3100582556 countsByYear W31005825562023 @default.
• W3100582556 crossrefType "journal-article" @default.
• W3100582556 hasAuthorship W3100582556A5005650204 @default.
• W3100582556 hasAuthorship W3100582556A5018416427 @default.
• W3100582556 hasAuthorship W3100582556A5033380392 @default.
• W3100582556 hasAuthorship W3100582556A5033714582 @default.
• W3100582556 hasAuthorship W3100582556A5034103646 @default.
• W3100582556 hasAuthorship W3100582556A5041709209 @default.
• W3100582556 hasAuthorship W3100582556A5042531886 @default.
• W3100582556 hasAuthorship W3100582556A5047640192 @default.
• W3100582556 hasAuthorship W3100582556A5060379321 @default.
• W3100582556 hasAuthorship W3100582556A5084686245 @default.
• W3100582556 hasAuthorship W3100582556A5086015666 @default.
• W3100582556 hasBestOaLocation W31005825561 @default.
• W3100582556 hasConcept C105083479 @default.
• W3100582556 hasConcept C126322002 @default.
• W3100582556 hasConcept C134018914 @default.
• W3100582556 hasConcept C141071460 @default.
• W3100582556 hasConcept C164705383 @default.
• W3100582556 hasConcept C181199279 @default.
• W3100582556 hasConcept C185592680 @default.
• W3100582556 hasConcept C193143273 @default.
• W3100582556 hasConcept C2776098176 @default.
• W3100582556 hasConcept C2777323849 @default.
• W3100582556 hasConcept C2779980429 @default.
• W3100582556 hasConcept C2779993416 @default.
• W3100582556 hasConcept C55493867 @default.
• W3100582556 hasConcept C71924100 @default.
• W3100582556 hasConceptScore W3100582556C105083479 @default.
• W3100582556 hasConceptScore W3100582556C126322002 @default.
• W3100582556 hasConceptScore W3100582556C134018914 @default.
• W3100582556 hasConceptScore W3100582556C141071460 @default.
• W3100582556 hasConceptScore W3100582556C164705383 @default.
• W3100582556 hasConceptScore W3100582556C181199279 @default.
• W3100582556 hasConceptScore W3100582556C185592680 @default.
• W3100582556 hasConceptScore W3100582556C193143273 @default.
• W3100582556 hasConceptScore W3100582556C2776098176 @default.
• W3100582556 hasConceptScore W3100582556C2777323849 @default.
• W3100582556 hasConceptScore W3100582556C2779980429 @default.
• W3100582556 hasConceptScore W3100582556C2779993416 @default.
• W3100582556 hasConceptScore W3100582556C55493867 @default.
• W3100582556 hasConceptScore W3100582556C71924100 @default.
• W3100582556 hasIssue "20" @default.
• W3100582556 hasLocation W31005825561 @default.
• W3100582556 hasLocation W31005825562 @default.
• W3100582556 hasOpenAccess W3100582556 @default.
• W3100582556 hasPrimaryLocation W31005825561 @default.
• W3100582556 hasRelatedWork W1981736657 @default.
• W3100582556 hasRelatedWork W1988068642 @default.
• W3100582556 hasRelatedWork W1990741035 @default.
• W3100582556 hasRelatedWork W2010600762 @default.
• W3100582556 hasRelatedWork W2081442501 @default.
• W3100582556 hasRelatedWork W2087090518 @default.
• W3100582556 hasRelatedWork W2123535222 @default.
• W3100582556 hasRelatedWork W2165460085 @default.
• W3100582556 hasRelatedWork W2318679753 @default.
• W3100582556 hasRelatedWork W3100582556 @default.
• W3100582556 hasVolume "142" @default.
• W3100582556 isParatext "false" @default.
• W3100582556 isRetracted "false" @default.
• W3100582556 magId "3100582556" @default.
• W3100582556 workType "article" @default.