Abstract
Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia (IH) and is a risk factor for cardiovascular diseases (e.g., atherosclerosis) and chronic inflammatory diseases (CID). The excessive proliferation of vascular smooth muscle cells (VSMCs) plays a pivotal role in the progression of atherosclerosis. Hypoxia-inducible factor-1 and nuclear factor-κB are thought to be the main factors involved in responses to IH and in regulating adaptations or inflammation pathways, however, further evidence is needed to demonstrate the underlying mechanisms of this process in VSMCs. Furthermore, few studies of IH have examined smooth muscle cell responses. Our previous studies demonstrated that increased interleukin (IL)-6, epidermal growth factor family ligands, and erbB2 receptor, some of which amplify inflammation and, consequently, induce CID, were induced by IH and were involved in the proliferation of VSMCs. Since IH increased IL-6 and epiregulin expression in VSMCs, the same phenomenon may also occur in other smooth muscle cells, and, consequently, may be related to the incidence or progression of several diseases. In the present review, we describe how IH can induce the excessive proliferation of VSMCs and we develop the suggestion that other CID may be related to the effects of IH on other smooth muscle cells.
Highlights
Obstructive sleep apnea (OSA) is characterized by repeated episodes of intermittent hypoxia (IH), i.e., transient oxygen (O2) desaturation, and resaturation
OSA is commonly diagnosed by polysomnography and its severity is classified by the apnea hypopnea index (AHI) as follows: mild, AHI ≥5; moderate, AHI ≥15; severe, AHI ≥30 [1,2]
In conjunction with the studies showing the involvement of Nuclear Factor (NF)-κB in IH, these results suggest that, in vascular smooth muscle cells (VSMCs), Hypoxia-Inducible Factor (HIF)-1 has more difficulty functioning in response to IH, as compared with NF-κB
Summary
Obstructive sleep apnea (OSA) is characterized by repeated episodes of intermittent hypoxia (IH), i.e., transient oxygen (O2) desaturation, and resaturation. A large number of previous in vivo and in vitro studies have shown that IH-induced intracellular mechanisms are mainly classified into two different transcription pathways, where the hypoxia-inducible factor (HIF)-1 and the nuclear factor (NF)-κB play central roles [16,33,38]. Several in vivo and in vitro studies have observed that IH induces the activation of NF-κB in cardiovascular tissues and endothelial cells [42,43,44,45]. Polotsky et al suggested that, in human aortic endothelial cells, IH (16% and 0% O2) and sustained hypoxia (4% O2) induced the mRNA expression of antioxidant genes, including heme oxygenase-1 and nuclear factor (erythroid-derived 2)-like 2 (NRF2), excluding HIF-1-related genes, such as endothelin and glucose transporter (GLUT)1 [67]. 44..IInntteerrlleeuukkiinn((IILL))--66 mni2achiioilTawpmfnceicfetadnnnnoedsn9haafeuheyxnloriofffcalshcccaejsltwopmetlllldrnvurolphttraaapsoeirsesrkooacooefksIe,mmmaeakoSOetpaahLcreSO((trstslhesnrsieph-hesntchlesreimmmu-neerαsiNoaevudsuseC6cuCsausevssierlus,eetlor,aaamsl,Fulic[eAAsfriaminrganis7ntttwtavilsi.a-reclnmaiiohnuetunShd5κvStucaooaelliyToliaarecMac–ltotMBoolvnrcpnncvyaofolhrlchst7dtnlhtcleieug,ilticcltvrCoashetC8filvicitl-iixauhar-dwnafionleorn]beyisoαebansopIsisrd.ocendinvel)dLait)dhrsvenitrCmicraoTirmsac[oam-[ieeeioiitagpt[na3kne67-ahcsasClhrisoshs3lfrs5ordschdk5iloleass,ee5ktaN-eosnsv]cud–ihesssdtiraIa]mo.itoxceinehaeat7leLsln.peeFucslefcalaSuinsrifcsa8elotwpel-mr-ilsSdgpr.airioiiscdar6cκ]osrotmcdvlnoicTrni.rouautdtiamBioseucoioetnfiaevfiiaeaslhTmnidplhviastnlsgndnlocnossceliapiesactheioelfonlerhhfiurdlnniiedtrahirewceeuvmosIarmnoroseallrfdrmrLtpsassamyesraIgamsnmliivtocsiumeLvy,net-yrvdettthnap-isaeh6aioeashieieo-,oeesoioyidtsunrnrnm1,dlitsdseddacnakdtonindeicntsi,8,dmuanysmucineomsrxi,itnoeseittnlanatcdheotmwincichicusiymfuephgnbtreumcancsefaliooaeadsoemuenseoepl,eestrntcordvitteacasierbml[nadeafohieaeiInplbaraea4sIlsinelnsHtstnieleHsniesIrer4ycsrihtnetntoatL,rresiadapsoiternd,rroeuaoogs6srfdonirnal-aigmiroIorcsntalsksu7o6ynacaIetLitndlasryunfocLtceIc,sieilfscscaet8a-esnHhlaatad-ercdu-ehttri6eyswed0dinIietns6ihtinseeinmrskmeLesvae],sau,daaidaaoefii.taaradintdeia-tosasrlc,msnsomne6n[nhasdTsIietitrenesid4pndswLsnotiodssdctdyhuirddugr4O,cahudea.grct-oasiewlnb,niian8InsteaIeIutn6ieISsroofcILsiLnnenheiedLteLee7arefciAienffIta-dtt-fiugoanLinl,eo-pfc8-Icarh6tst8clr6,a1IusssHcnetrhdu-aeraea0Ltwssceai68aanileliccilihelsscn]ilntannn-dlnannswteun.srd,u,itasie8ttitrweflcdiionlstiiicohmnelhhsvalTinnrncasoctaaseutcwoanudenecasuoirnhhpnctdmbIoamtprlroai,tImdHrlmidasheadeapheIroHemOtsroardmuLrsursrthseerrteoeiatfaieuethniSg-oaielsrlesnaaanho[oonalhe8taaesAiItd7gssnautcafoaenfdnriaHtovsiic9e[tfcntunttietrosn-tdot8himuoieioso]sodo3yars.svceonn.1citertnnmahcruneyboIsatnehwdi(wo–hsortvnnhcsaaeaSsleutohi8eoounitetneisrotivaleoeiTnsissia3tlayefftaacecsnasoanfetneAhahe]sdetrrrsgaaeaOrdcnfbsOc/iytiisaTocIlssyupbOmuupstONjmoaHSsidtbuaw,Ss3elalasagtoimtaSAayeuSsswiFv)Aieis.horrnfgrsion,AtcessAtalnt-atmlaTtied2ee,aetwreκntwNehocetwa,ueaa9vlahsduricBraronlsni3mdohstiFytneeiupyisntmiitaobenretlndii-indneh(oloodtihscIsescoκsoesSescsdhcecLfohmpoerlitumnBciusTeratinauiieoi-inrrpuah,naecnnnn6sitAotdvafvm(oIfrn,eli-aboflfleflvflaHltodaveaaeaiotrTsscaoIhm/aanohiaadteactrnmeiHeptrma3tihsomsrmtsmadsmheeohasaeai)ruvypchi[anvmn,lo[mrinmnmmm7mNtychsal8lssiytweaas-itiun9atusesk1aubvicutfipctaaeauFabncu]ihacsit–mrsaramtsmset.ototu-oosolgsti8siiosotictκerfhnxcocnrioloetesohea3liorrasaiBhlhyiiineeecsssdrnnnf]yyee.cssrrr, bcootnhdNitiFo-nκsB) (avnida hSTyApoTx3ic(vcioanindcitrieoansse)daInLd-6S)T[A34T,335(,v4i3a,6i1n,c8r3e]a. sed IL-6) [34,35,43,61,83]. osmtptrfmoichfoersfaaoscaaeacvutegymhrtpeperIhoIefnnrestnaepcoo,sgrceahsgparIeoildiHsaldrrlrosiedgotcdsnfrsameliugoieestttorrciceirifaoemofoheooymsnnnpasasaaitftmiattstoshoaoooic.fcoersnrcisiircanolnneoaitpsolftflhsv[laulh8fcaaeetfcl4ammrenoeha]gorgr.mtmmesomhaecGsafasrealaioectrtsirtisaiorvr.eioocoomosecnanpscnnev,i,lhpcsetet[teh.atrh8nhloogeL4legerse]ficeic.koAirsrfrnGere.oemcarlaaaiyreLtvnmte,iaciioedaIoteknnLispcneoCee-ltont6ysoloDhfls,frpeom3fimoafn6AIiaLrrn,IaltcmL-iceiacr6nars-ronae6liomptdloapiypfhnosaarhCeacnsorcasgo,tDsrmigaenoaoi3enptnlff6Vlrodfhy,iIloaSbLeatimaMuhsng-cm6iteoeoCecmrsnfnesec,srtlsaeboartl,calsoiynmlbransidoicunsdniopVdtslacenihoSlrkaststaetMhlerohgsailetobeyseCaorerusnesais,tnbvniieanaimydannnictsumopcdrdcmceooupteaonhlralosistattejkaehrormretinsperablttrarynisuioscfcnvttesrgiaeanafuorvestmdpteeueacosshunturas,uteacgiljhIooaergeoHeesrrnerf
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