Tshooj 1 Cov Teeb Meem Thiab Cov Mechanisms Ntawm Suav Herbal Tshuaj hauv Ameliorating Myocardial Ischemia-Reperfusion Injury

Qing Liu, 1,2 Jiqiang Li, 2 Jing Wang, 2 Jianping Li, 1 Joseph S. Janicki, 1 thiab Daping Fan1

1 Department of Cell Biology thiab Anatomy, University of South Carolina Tsev Kawm Ntawv Tshuaj, Columbia, SC 29208, USA

2 Lub Tsev Kawm Ntawv Kho Mob Thib Ob ntawm Tshuaj, Guangzhou University ofSuav Tshuaj, Guangzhou 510405, Suav teb

Cov ntawv xov xwm yuav tsum tau hais rau Daping Ntxuam; daping.fan@uscmed.sc.edu Tau txais 24 Lub Xya Hli 2013; Hloov kho 26 Lub Yim Hli 2013; Tau txais 4 Cuaj hlis 2013 Kev Kawm Editor: John-Rong Sheu

Copyright © 2013 Qing Liu et al. Qhov no yog ib tsab xov xwm qhib nkag tau muab faib raws li Creative Commons Attribution License, uas tso cai rau kev siv tsis txwv, kev faib tawm, thiab luam tawm hauv ib qho nruab nrab, yog tias cov haujlwm qub raug suav hais tias yog.

Myocardial ischemia-reperfusion (MIR) raug mob yog ib qho tseem ceeb rau kev mob thiab kev tuag uas cuam tshuam nrog cov kab mob plawv, uas suav txog kwv yees li 450,000 tuag ib xyoos hauv Tebchaws Meskas ib leeg.Suav tshuaj ntsuab, tshwj xeeb tshaj yog ua ke tshuaj ntsuab formulations, tau dav siv nyob rau hauv ib txwmSuav tshuajrau kev kho mob ntawm myocardial infarction rau ntau pua xyoo. Thaum qhov ua tau zoo ntawmSuav tshuaj ntsuabyog cov ntaub ntawv zoo, lub hauv paus molecular mechanisms tseem elusive. Hauv qhov kev tshuaj xyuas no, peb hais txog cov kev tshawb fawb tsis ntev los no uas tau tsom mus rau elucidating cellular thiab molecular mechanisms siv cov tshuaj rho tawm, tshuaj ntsuab ib leeg, lossis tshuaj ntsuab formulations hauv kev sim. Cov kev tshawb fawb no sawv cev rau kev siv zog tsis ntev los no los txuas qhov sib txawv ntawm qhov enigma ntawm ancientSuav tshuaj ntsuabthiab cov ntsiab lus ntawm niaj hnub cell thiab molecular biology nyob rau hauv kev kho mob ntawm myocardial infarction.

Yog xav paub ntxiv thov hu rau:Joanna.jia@wecistanche.com

Cistanche deserticola muaj ntau yam teebmeem, nyem qhov no kom paub ntau ntxiv

1. Taw qhia

Myocardial infarction (MI) thiab qhov ua rau poob ntawm qhov muaj peev xwm myocardium yog qhov ua rau tuag hauv cov teb chaws uas muaj kev lag luam. Txawm hais tias tus neeg mob muaj sia nyob rau theem mob hnyav ntawm MI, qhov kev hloov pauv ntawm myocardial tsis zoo thiab kev ua haujlwm tsis zoo ntawm lub plawv ua rau lawv lub neej zoo thiab 5- xyoo ciaj sia. Kev kho thaum ntxov ntawm cov ntshav ntws mus rau ischemic myocardium yog ib qho kev kho mob uas siv los txo qhov loj ntawm myocardial infarct. Txawm li cas los xij, reperfusion tuaj yeem ua rau cov cell tuag ntxiv thiab, ntau zaus, paradoxically nce infarct loj, qhov xwm txheej hu ua myocardial ischemia-reperfusion (MIR) raug mob. MIR yog tus cwj pwm los ntawm kev nce nrawm ntawm cytokines thiab chemokines thiab cov leukocytes nkag mus rau hauv thaj tsam tsis muaj zog uas ciam teb rau qhov chaw infarcted. Qhov no inflammatory teb tsis tsuas yog ua rau cardiomyocyteapoptosisThaum lub sij hawm mob hnyav tab sis kuj ua rau muaj kev cuam tshuam tsis zoo ntawm myocardial remodeling uas ntxiv cuam tshuam rau lub plawv ua haujlwm. Yog li ntawd, txwv tsis pub ischemia-reperfusion (I / R) ua rau mob myocardial o tuaj yeem tsis tsuas yog txo qis tus mob tuag tab sis kuj txhim kho txoj sia nyob mus ntev thiab kev ua neej zoo [1]. Suav tshuaj ntsuab, tshwj xeeb tshaj yog ua ke herba formulations tau dav siv hauv cov tshuaj suav tshuaj rau kev kho mob ntawm MI rau ntau pua xyoo. Lub hom phiaj ntawm qhov kev tshuaj xyuas no yog los qhia txog cov kev tshawb fawb tsis ntev los no uas tau sim hais txog qhov cuam tshuam ntawm cov khoom sib txuas, tshuaj ntsuab ib leeg, lossis tshuaj ntsuab formulations ntawm ntau yam thiab txoj hauv kev paub tias muaj feem cuam tshuam nrog MIR raug mob.

2. Myocardial Ischemia-Reperfusion Injury

2.1. Oxidative Stress.

Reactive oxygen hom (ROS) muaj ob qho tib si physiological thiab pathological lub luag haujlwm hauv cellular thiab cov ntaub so ntswg hloov mus rau ib puag ncig yam. Feem ntau, qis qis ntawm cov pa oxygen radicals thiab oxidants muaj nyob hauv cov hlwb thiab tseem ceeb hauv kev tswj hwm cellular homeostasis, mitosis, sib txawv, thiab teeb liab [2]. Txawm li cas los xij, thaum lub sij hawm MIR, ROS tsim tau nce zuj zus thiab kev raug mob ntawm tes tshwm sim (Daim duab 1). Txawm hais tias cov kab mob mammalian nthuav tawm endogenous dawb radical scavenging enzymes, xws li superoxide dis- mutase (SOD), catalase (CAT), thiab glutathione peroxidase (GPx), cov tshuaj tiv thaiv oxidative tsis txaus thaum MIR [3, 4]. Oxidative stress thaum MIR raug mob ua rau lub voj voog tsis zoo vim nws txhawb nqa mitochondrial tsis ua haujlwm, excitotoxicity, lipid peroxidation, thiab o [5-7].

2.2. Sterile Inflamation.

Ischemia thiab reperfusion ua rau tsis muaj menyuam. Txawm li cas los xij, qhov tshwm sim ntawm MIR qhia ntau qhov sib txawv ntawm phenotypic nrog kev ua kom lub cev tiv thaiv kab mob rau cov kab mob invading [8]. Qhov mob tsis zoo no feem ntau tshwm sim los ntawm kev sib cuam tshuam ntawm tus xov tooj zoo li receptors (TLRs) thiab lawv cov ligands endogenous generated hauv ischemic thiab reperfused myocardium, xws li apoptotic cell khib nyiab, fibrinogen, high mobility group box (HMGB) 1, thiab kub poob siab proteins ( HSP) [9]. Kev ua kom lub cev tiv thaiv kab mob thiab cardiomyocyte TLR thiab lwm yam kev taw qhia ua rau lub voj voog tsis zoo ntawm cov lus teb hauv cheeb tsam I / R thiab ua rau muaj qhov tseem ceeb cardiomyocyte.apoptosis(Daim duab 1). Tom qab lub sijhawm I / R mob hnyav, lub plawv ua haujlwm tau cuam tshuam ntxiv los ntawm kev hloov kho myocardial tsis zoo [10]. Qhov loj ntawm qhov mob thaum lub sij hawm mob hnyav txiav txim siab txog qhov twg lub plawv ua haujlwm raug cuam tshuam thaum lub sijhawm kho myocardial hauv qab no. Thaum lub sij hawm sterile o theem ntawm MIR, TLRs ua lub luag haujlwm tsis zoo raws li tau pom los ntawm kev sim ntau yam pov thawj [11]. Txog niaj hnub no, 11 TLRs (TLR1–TLR11) tau raug txheeb xyuas hauv cov tsiaj txhu. Nws yuav tsum tau muab sau tseg tias, thaum lub sij hawm MIR, qhov kev qhia ntawm TLR4 yog nce ntau nyob rau hauv ob qho tib si myocardium tsis ua hauj lwm thiab infiltrated macrophages thiab yog li TLR4 yog xav tias yog lub hauv paus nruab nrab ntawm o thiab mob plawv. TLR4 tau raug txheeb xyuas tias yog tus neeg nruab nrab ntawm kev mob thiab kev raug mob ntawm lub cev hauv ntau cov qauv ntawm cov ntaub so ntswg tsis huv nrog rau MIR, thiab cov tshuaj tiv thaiv soluble ntawm TLR4 muaj peev xwm tiv thaiv kev ua haujlwm tsis zoo hauv cov hlwb qus [12]. Siv ib ntus sab laug anterior descending (LAD) artery occlusion qauv, Oyama li al. thawj zaug pom myocardial infarct loj txo nyob rau hauv 2 txawv hom nas uas tsis muaj kev ua haujlwm TLR4 signaling, nrog rau txo neutrophil infiltration hauv cov cuam tshuam myocardium [13]. TLR2, uas tau nthuav tawm hauv cardiomyocytes thiab ntau lwm hom ntawm tes, kuj tseem ua rau cov kab mob ntawm lub plawv tsis ua haujlwm thaum MIR [14, 15]. Ua kom TLR2, TLR4, thiab TLR5 ua rau kom cov qib myocardial ntawm cov inflammatory cytokines, chemokines, thiab cell nto adhesion molecules [16]. Muab lub luag haujlwm paub txog TLR4 thiab TLR2 hauv MIR, inhibition ntawm TLR4 thiab TLR2 signaling yog ib txoj hauv kev zoo los txo cov neeg mob thiab kev tuag hauv cov neeg mob MI. Muaj ntau yam ntawm TLR ligands tsim thaum lub sij hawm MIR. Piv txwv li, heat shock proteins (HSPs) yog ib chav kawm ntawm molecular chaperones uas txhawb nqa cov protein folding intracellular. Lawv tuaj yeem raug tso tawm rau hauv qhov chaw ntxiv tom qab kev raug mob ntawm tes thiab cuam tshuam nrog cov cell uas nyob ib sab lossis cov hlwb nyob deb ntawm cov hlab ntshav xa mus [17]. Extracellular HSP60 inducedapoptosislos ntawm kev ua kom TLRs [18]. Lwm qhov piv txwv yog HMGB1 uas yog kev puas tsuaj rau cov qauv molecular (DAMP) cov protein uas zais los ntawm cov hlwb raug mob [19]. Nws ua lub luag haujlwm tseem ceeb hauv MIR thaum ntxov los ntawm kev khi rau TLRs thiab cov receptor rau qib siab glycation kawg cov khoom (RAGE), uas ua rau muaj kev ua kom muaj zog ntawm txoj hauv kev thiab txhim kho myocardial raug mob [20]. Qhov tseeb, qhov yuav tsum tau ua ua ntej rau kev puas tsuaj rau cov ntaub so ntswg neutrophil yog qhov "priming" cov nyhuv ntawm ntau yam pro-inflammatory stimuli generated los ntawm cov ntaub so ntswg-laus thaum MIR, xws li HSP60 thiab HMGB1 [21]. Cytokines tso tawm los ntawm TLR-activated hlwb xws li qog necrosis factor-alpha (TNF-) thiab IL-1 tuaj yeem elicit neutrophil polarization thiab upregulation ntawm cell-surface glycoproteins xws li macrophage adhesion molecule-1 (Mac{{ 17}}) [22]; Mac{19}} upregulation nyob rau hauv peripheral neutrophils yog ib qho kev tshwm sim ntxov heev hauv MIR [23].

Anti-apoptosisnyhuv ntawmCistanchedeserticolarho tawm

2.3. Apoptosis thiab Mitochondrial Function.

MIR ua rau kev ua kom cov kev pabcuam cell tuag, suav nrogapoptosis, autophagy-associated cell tuag, thiab necrosis [24].ApoptosisNws suav nrog kev ua haujlwm caspase signaling cascade, suav nrog caspase -3 thiab caspase-9, uas ua rau nws tus kheej muaj cov kev pab cuam ntawm cov cell tuag, tus cwj pwm los ntawm kev txo qis ntawm cov cell thiab nws cov nucleus, nrog rau cov plasma membrane kev ncaj ncees mus txog thaum lig nyob rau hauv tus txheej txheem [25] Qhov sib npaug ntawm apoptotic yam Bcl-2 thiab Bax tau pom tau hloov pauv hauv cardiomyocytes thaum ischemia [26]. Autophagy yog txhawb nqa los ntawm kev tshaib plab thiab kev loj hlob ntawm kev loj hlob thaum lub hlwb tsis tuaj yeem nqa cov khoom noj sab nraud. Autophagy kuj tseem qhib los ntawm kev txo qis hauv ATP txhawm rau kom lub cell kom muaj zog homeostasis thiab ciaj sia. Autophagy tuaj yeem ua haujlwm feem ntau los tswj kev tsim hluav taws xob thaum lub sij hawm mob ischemia tab sis hloov mus tshem tawm cov kab mob uas puas lawm thaum lub sij hawm mob ischemia ntawm reperfusion [27]. Ntau lub xov tooj ntawm tes taw qhia txoj hauv kev, xws li AMPK, JNK, thiab NF-𝜅B txoj hauv kev, tau pom tias koom nrog hauv MIR-induced cardiomyocyte.apoptosis(Daim duab 1). AMPK orchestrates cov kev cai ntawm kev tsim hluav taws xob thiab kev siv hluav taws xob; nws qhov kev ua kom tau pom tias tiv thaiv lub plawv tiv thaiv kev raug mob ischemic [28, 29]. Ua kom JNK signaling, tshwj xeeb tshaj yog nyob rau hauv mitochondria, yog txuam nrog oxidative kev nyuaj siab, mitochondrial dysfunction, thiab cell tuag [30]; Nws yog qhov kev hloov pauv tseem ceeb hauv kev tuag ntawm tes los ntawm cov pa oxygen reactive thiab nitrogen hom [31]. JNK tseem xav tau rau TNF-𝛼-stimulated ROS ntau lawm thiab cytochrome c-mediated cell tuag; Bcl{10}} cov neeg hauv tsev neeg yog cov khoom tseem ceeb ntawm cov tshuab mitochondrial apoptotic no. Cov kev tshawb fawb tau qhia tias kev thaiv ntawm JNK mitochondrial translocation los yog JNK inhibition tiv thaiv ROS ntau lawm thiab mitochondrial dysfunction thiab tej zaum yuav yog ib qho kev kho mob zoo rau I / R-induced cardiomyocyte tuag [32–35]. Lub nuclear factor kappa B (NF-B) kuj modulates apoptosis thaum ischemia thiab reperfusion [36]. TLR signaling pathway ua rau kev hloov pauv ntawm NF-𝜅B mus rau lub nucleus thiab yog li nce-txoj cai ntawm kev qhia ntawm proinflammatory cytokines. Txawm li cas los xij, nws muaj peev xwm hais tau tias crosstalk ntawm TLR / NF-B thiab PI3K / Akt qhia txoj hauv kev thiab kev hloov pauv ntawm crosstalk tuaj yeem tiv thaiv myocardium los ntawm I / R raug mob [37]. Nyob rau hauv txoj kev mitochondria-dependent intrinsic apoptosis txoj kev, uas muaj ib qho tseem ceeb hauv kev raug mob ntawm lub plawv nyob rau hauv ntau yam kab mob pathological [38], mitochondrial permeability transition pore (MPTP) qhib plays lub luag haujlwm tseem ceeb [39]. Qhov kev tshwm sim ntawm MPTP qhib yog cuam tshuam los ntawm ntau yam xws li intracellular Ca2 ntxiv, oxidative radicals, ATP qib, thiab qib Bcl -2 tsev neeg cov proteins [40]

Echinacoside hauvcistanchetxhawb nqativ thaiv kab mobqhov system

2.4. Bone Marrow Stem Cell Migration.

Cov pob txha pob txha mesenchymal qia hlwb (BMSCs) yog cov hlwb ntau lub zog uas zais cov yam ntxwv ntawm angiogenic. Cov ntaub so ntswg uas raug mob qhia cov receptors tshwj xeeb, xws li CXCR4, thiab / lossis lawv cov ligands suav nrog stromal cell-derived factor-1 (SDF-1), los pab txhawb kev lag luam, adhesion, thiab infiltration ntawm BMSCs. Thaum lub sij hawm MIR, BMSCs nyiam nyiam thiab khaws cia hauv cov ntaub so ntswg ischemic [41, 42]. Raws li qhov tshwm sim ntawm hypoxic microenvironment, BMSCs no tsim cov qib vascular endothelial loj hlob zoo tshaj plaws (VEGF), ua rau muaj kev nce hauv cov hlab ntsha thiab pab txhawb kev tsim kho myocardial thiab kho dua tshiab [43, 44] (Daim duab 1). 2.5. Angiogenesis. Angiogenesis yog hais txog kev tawg, kev sib txuas, kev nkag siab, thiab / lossis kev loj hlob ntawm capillaries. Nyob rau theem kawg ntawm kev kho MI, kev txhim kho cov ntshav ntws mus rau ischemic myocardium tuaj yeem tshwm sim los ntawm qhov tseeb angiogenesis lossis kev nrhiav neeg ua haujlwm ntawm cov khoom lag luam coronary [45]. VEGF yog endothelial cell-specific angiogenic yam tseem ceeb thiab tseem yog ib qho tseem ceeb regulator ntawm angiogenesis uas nkoos proliferation, migration, thiab proteolytic kev ua ntawm endothelial hlwb [46]. Ischemia lossis coronary artery occlusion induces myocardial VEGF qhia, uas ua rau angiogenesis-induced restoration ntawm cov ntaub so ntswg ntshav khiav thiab tiv thaiv cov ntaub so ntswg puas lawm (Daim duab 1). Tsis tas li ntawd, VEGF yog ib qho tseem ceeb ciaj sia taus thaum lub sij hawm physiological thiab qog angiogenesis thiab tau pom los induce qhov kev qhia ntawm anti-apoptotic proteins nyob rau hauv endothelial hlwb [47, 48].

2.5. Lwm yam Factors.

Kev ua kom muaj ATP-sensitive potassium (KATP) channel subunits thiab ATPase, thiab calcium (Ca2 ntxiv) 4 Cov Ntawv Pov Thawj-Raws Li Ntxiv thiab Lwm Cov Tshuaj Tshaj Tawm kuj koom nrog hauv MIR (Daim duab 1). Ischemia-reperfusion tuaj yeem qhib qee cov ion channel uas tsis qhib raws li cov xwm txheej ntawm lub cev. Ib qho channel zoo li no yog KATP channel, uas nws qhov kev ua kom yooj yim rau cov poov tshuaj ion efflux, hyperpolarization, thiab kev ua kom muaj peev xwm rov ua dua. Qhov ua rau luv luv ntawm qhov kev txiav txim siab lub sijhawm ua rau txo qis tag nrho cov khoom siv ntawm sodium thiab calcium, uas ua rau txo qis ntawm cov calcium ntau dhau ntawm cov cellular (Ca2 ntxiv) uas ua rau muaj zog myocardial contraction force thiab txo cov kev siv cov pa oxygen hauv myocardial. Yog li ntawd, kev qhib KATP channel plays lub luag haujlwm tseem ceeb hauv kev tiv thaiv lub plawv tiv thaiv kev raug mob MIR.

Txhawm rau tiv thaiv kab mob raum thiab mob qog noj ntshav nrogcistanche