Mineralocorticoid Receptor Activation Thiab antagonism nyob rau hauv Kab Mob plawv: Cellular Thiab Molecular Mechanisms
Jul 07, 2022
Aldosterone tswj cov dej ntsev-dej homeostasis los ntawm kev ua ntawm cov mineralocorticoid receptor (MR), ligand-activated transcription factor, nyob rau hauv lub raum epithelial hlwb. Txawm li cas los xij, tam sim no tau pom tseeb tias MR tau nthuav tawm ntau hom cell thiab cov ntaub so ntswg, ua tus tsav tsheb tseem ceeb ntawm cov kab mob plawv. MR antagonists tau ua pov thawj tias muaj txiaj ntsig zoo rau cov neeg mob uas muaj lub plawv tsis ua haujlwm thiab txo qis ejection feem, thiab lawv yog lub hauv paus ntawm kev kho mob tam sim no. Nyob rau hauv kaum xyoo dhau los, ib tug series ntawm kev sim kev tshawb fawb siv cov qauv nrog cell hom-specific MRS uncovered cellular thiab molecular mechanisms nyob rau hauv lub hauv paus ntawm nws detrimental cuam tshuam rau sab laug ventricular remodeling. Raws li cov kev tshawb pom no, lub peev xwm ntawm MR antagonists tau raug soj ntsuam hauv lwm cov kab mob plawv, nrog rau cov kab mob hauv cov hlab ntsha, cov hlab ntshav siab, plawv tsis ua hauj lwm nrog kev khaws cia ejection feem, pulmonary hypertension, atrial fibrillation, thiab kab mob plawv. Qhov kev tshuaj xyuas tam sim no qhia txog cov kev paub tam sim no ntawm MR kev ua kom thiab kev tawm tsam hauv cov kab mob plawv.
Nyem rau maca ginseng cistanche rau lub raum
Aldosterone, ib qho tshuaj steroid uas tsim los ntawm zona glomerulosa hlwb ntawm adrenal cortex, yog ib qho tseem ceeb ntawm cov tshuaj hormones ntawm renin-angiotensin-aldosterone system.1,2 Lub luag haujlwm ntawm lub cev ntawm aldosterone yog tswj hwm ntsev- dej homeostasis los ntawm kev ua ntawm cov mineralocorticoid receptor. (MR), ligand-activated transcription factor, nyob rau hauv lub raum epithelial hlwb. Aldosterone ntawm MR ua rau kev txhim kho thiab ua kom cov amiloride-sensitive epithelial Naþ channel, yog li ua kom Naþ reabsorption thiab Kþ secretion.2 Thawj MR antagonist (MRA), spironolactone, tau tsim los ua cov tshuaj tiv thaiv kab mob, nrog rau lub hom phiaj los tiv thaiv Naþ. tuav thiab txo cov ntshav ntim.3,4 Txawm li cas los xij, vim tias nws cov haujlwm ntawm progesterone receptors thiab lwm yam receptors nuclear, spironolactone tuaj yeem ua rau muaj kev phiv cuam tshuam, xws li gynecomastia.3 Cov nyhuv no tuaj yeem ameliorated los ntawm lub thib ob tiam compound eplerenone thiab, Tsis ntev los no, chav kawm tshiab ntawm kev xaiv ntau, muaj zog uas tsis yog tshuaj steroidal MRAs. xws li fifinerenone thiab esaxerenone.3,4
Johann Bauersachs1 thiab Achim Lother 2,3
1 Department of Cardiology thiab Angiology, Hannover Medical School, Hannover, Lub teb chaws Yelemees;
2 Department of Cardiology thiab Angiology I, University Heart Center, Medical Center – Kws Qhia Ntawv ntawm Tshuaj, University of Freiburg, Freiburg, Lub teb chaws Yelemees; thiab
3 Lub Tsev Kawm Ntawv ntawm Kev Tshawb Fawb thiab Kev Kho Mob Pharmacology thiab Toxicology, Kws Qhia Ntawv ntawm Tshuaj, University of Freiburg, Freiburg, Lub Tebchaws Yelemees
Kev tiv thaiv kab mob plawv ntawm MRAs yog thawj zaug los ntawm lawv cov teebmeem ntawm diuresis, ntshav ntim, thiab electrolyte homeostasis.5 Txawm li cas los xij, MR tau nthuav tawm ntau hom cell thiab cov ntaub so ntswg sab nraum lub raum, thiab tam sim no pom tseeb tias MR hauv cov ntaub so ntswg extrarenal yog. tus neeg tsav tsheb tseem ceeb ntawm cov kab mob (Daim duab 1.6,7 Ntau tshaj 20 xyoo dhau los, kev sim tshuaj loj tau muab pov thawj tias kev kho MRA txhim kho kev tuag thiab mob rau cov neeg mob plawv tsis ua hauj lwm nrog txo qis ejection feem (HFrEF), ua rau cov chav kawm IA cov lus qhia. kev pom zoo.8–10 Txij thaum ntawd los, cov kev tshawb fawb kev sim tau nthuav tawm cov xov tooj ntawm tes thiab cov tshuab molecular hauv qab cov txiaj ntsig zoo ntawm sab laug ventricular (LV) hloov kho. Raws li cov kev tshawb pom no, lub peev xwm ntawm MRAs tau raug soj ntsuam hauv lwm cov kab mob plawv, nrog rau cov kab mob plawv, ntshav siab, plawv tsis ua hauj lwm nrog khaws cia ejection feem (HFpEF), pulmonary hypertension (PH), thiab kab mob plawv. Qhov kev tshuaj xyuas tam sim no qhia txog cov kev paub tam sim no ntawm MR kev ua kom thiab kev tawm tsam hauv cov kab mob plawv.
HFrEF thiab post-myocardial infarction remodeling MRAs tau tsim cov tshuaj nyob rau hauv kev kho mob ntawm HFrEF ntev, raws li muaj pov thawj nyob rau hauv ntau yam kev tshawb fawb.8 Eplerenone nyob rau hauv me me cov neeg mob nyob rau hauv tsev kho mob thiab ciaj sia txoj kev kawm nyob rau hauv lub plawv tsis ua hauj lwm (EMPHASIS-HF) pom tau hais tias ib tug txo nyob rau hauv kev tuag los ntawm 24 feem pua. Hauv cov neeg mob uas muaj HFrEF thiab cov tsos mob me tau kho nrog eplerenone piv rau cov placebo.11 Hauv Randomized Aldactone Evaluation Study (RALES), spironolactone tau muaj txiaj ntsig zoo sib xws hauv cov neeg mob uas muaj cov tsos mob plawv tsis ua haujlwm hnyav, uas cov neeg tuag tau txo los ntawm 30 feem pua ntawm cov placebo.12 Kev tshawb fawb tau qhia tias, zoo li spironolactone thiab eplerenone, cov nonsteroidal MRA finerenone txo qis qib ntawm pro-B-type natriuretic peptide (BNP) los yog N-terminal BNP (NT-proBNP) nyob rau theem II trials.13,14 Thaum ntxov pib ntawm MRA kev kho mob hauv Cov neeg mob uas mob plawv tsis ua hauj lwm tau pom tias muaj kev nyab xeeb thiab ua tau zoo.15,16 Eplerenone txhim kho cov txiaj ntsig ntawm cov neeg mob uas muaj qhov tsis zoo LV ua haujlwm tom qab myocardial infarction (MI).1 7 Cov kev tshawb fawb tom qab tau sim qhov kev xav tias qhov pib ntawm MR blockade thaum ntxov tom qab MI tuaj yeem tiv thaiv kev kho plawv thiab qhov tshwm sim ntawm lub plawv tsis ua haujlwm. Thaum pib li ntawm 72 teev tom qab qhov tsos mob tshwm sim, kev kho MRA tau txhim kho BNP / NT-proBNP qib hauv cov neeg mob uas tsis muaj lub plawv tsis ua haujlwm ua ntej.18 Txawm li cas los xij, hauv kev tshawb fawb tom qab, muaj txiaj ntsig zoo ntawm kev kho MRA thaum ntxov ntawm cov txiaj ntsig kho mob tau pom tsuas yog hauv pawg pawg ntawm Cov neeg mob uas muaj kev pheej hmoo siab nrog ST-elevation MI.19 Ib tus neeg mob-theem meta-kev soj ntsuam ntawm 3 qhov loj randomized tswj kev sim hauv cov neeg mob nrog HFrEF kuj pom tau tias txo qis 23 feem pua ntawm kev tuag sai sai nrog kev kho MRA.20 Hauv cov neeg mob uas tau kuaj HFrEF tshiab. , kev kho mob nrog ntau dua MRA tau cuam tshuam nrog kev ua kom zoo dua ntawm LV ejection feem ntau dhau 3 lub hlis.21
Kev sim kev tshawb fawb siv MRAs hauv cov qauv tsiaj ntawm lub plawv tsis ua hauj lwm thiab kev kho mob tom qab MI tau pom tias muaj txiaj ntsig zoo ntawm kev mob plawv hypertrophy, fifibrosis, lossis ob qho tib si (Daim duab 1). Cov teebmeem no tau kho los ntawm kev ua kom MR hauv cov hlab plawv. MR tshem tawm ntawm lub plawv myocytes ua rau me me caws pliav, tsawg fifibrosis ntawm tej thaj chaw deb cov ntaub so ntswg, thiab txhim kho LV muaj nuj nqi.26 Txo fifibrosis tom qab ischemic raug mob yog txuam nrog attenuated oxidative kev nyuaj siab thiab myocyte apoptosis, tab sis ntau dua cov neutrophils thiab monocytes tau kuaj pom nyob rau hauv myocardial. Cov ntaub so ntswg los ntawm MR-tsis muaj cov nas piv nrog cov nas qus.26 Qhov tshwj xeeb, MR tshem tawm ntawm cov hlwb myeloid zoo li txhim kho LV hloov kho thiab ua rau muaj kev hloov pauv mus rau ntau-reparative M2 macrophage subtype.27 MR tshem tawm ntawm cov leeg nqaij leeg (SMCs) attenuated LV fifibrosis tab sis muaj kev cuam tshuam me me ntawm LV muaj nuj nqi.25 Qhov no txhais tau hais tias MRAs muaj kev cuam tshuam rau ntau hom cell uas ua rau muaj kev cuam tshuam rau kev puas tsuaj thiab kho tom qab MI.
Lub hauv paus ntawm kev mob tshwm sim hauv kev kho kom haum rau cov txiaj ntsig zoo ntawm MR ua kom tau txais kev pom zoo hauv cov qauv ntawm lub plawv tsis ua haujlwm ntev (Daim duab 2). L-arginine methyl ester (L-NAME)/angiotensin II infusion.28,29 Cov txiaj ntsig zoo sib xws tau pom hauv cov nas uas tsis muaj MRS hauv T cells.30 Tsis ntev los no, SMC MR tshem tawm tau pom tias txhim kho lub siab dhau ntawm LV hypertrophy, mob, fifibrosis, thiab dysfunction.31 MR deletion ntawm endothelial hlwb los yog cardiac myocytes txhim kho LV muaj nuj nqi, tab sis nyob rau hauv sib piv rau ischemic raug mob, nws tsis tswj fifibrosis tom qab siab overload.32,33 Tsis muaj qhov sib txawv tom qab MR tshem tawm ntawm fibroblasts.32 Cov kev tshawb pom no qhia tias qhov cuam tshuam ntawm MR ntawm kev kho mob plawv nyob ntawm tsis yog hom cell xwb tab sis kuj yog hom kev raug mob.
Kev siv zog ntau heev tau ua los txiav txim siab molecular tswj cov txheej txheem tom qab aldosterone / MR-induced LV remodeling. Cov yam ntxwv zoo inflammatory thiab fibrotic effector molecules ntawm MR nyob rau hauv cov hlab plawv system muaj xws li galectin 3 (LGALS3) thiab lipocalin 2 (NGAL). remodeling.55,56 Plasma theem ntawm NGAL tau zoo correlated nrog circulating aldosterone theem thiab fifibrosis biomarkers nyob rau hauv tib neeg.57 Tshem tawm NGAL los ntawm lub cev tiv thaiv kab mob tiv thaiv LV fifibrosis nyob rau hauv teb rau aldosterone infusion.58 Ib yam li ntawd, MR deletion los ntawm myelac remodel hlwb txhim kho. myocardial infarction, uas tau cuam tshuam nrog txo NGAL qhia hauv plawv macrophages.27 Kev tshuaj ntsuam xyuas siab dhau los ntawm microRNAs tsis ntev los no tau txheeb xyuas miR-181a raws li tus tswj hwm tseem ceeb ntawm MR signaling.59 miR-181ib qho overexpression downregulated NGAL qhia hauv vitro thiab hauv vivo thiab txhim kho lub plawv ua haujlwm hauv nas MI qauv.59
HFpEF Feem ntau ntawm HFpEF nce ntxiv thiab twb muaj ntau dua 50 feem pua ntawm cov mob plawv tsis ua hauj lwm.60 Txawm tias muaj cov tsos mob sib tshooj, HFpEF suav tias yog ib qho chaw cais los ntawm HFrEF.60 Piv nrog rau cov neeg mob HFrEF, cov neeg mob HFpEF laus dua, ntau dua. Feem ntau cov poj niam thiab rog, thiab muaj ntau yam sib txawv, xws li ntshav qab zib thiab kab mob raum, uas cuam tshuam nrog kev mob ntev.60,61 MR kev ua kom oxidative stress thiab impairs nitric oxide (NO) signaling, ua rau endothelial dysfunction, inflammation, thiab perivascular. fifibrosis.34 Txawm hais tias qhov zoo tshaj plaws preclinical qauv los kawm HFpEF tseem yuav raug txhais, ib qho kev tshawb pom tseeb yog tias MR ua kom muaj feem xyuam nrog ntau yam ntawm cov kab mob pathophysiological uas ua rau HFpEF.62,63 MRAs txhim kho diastolic dysfunction induced los ntawm rog, ovariectomy, nephrectomy. los yog deoxycorticosterone acetate (DOCA) / ntsev ntshav siab hauv nas.64–67 Cell hom-specific MR tshem tawm ntawm lub plawv myocytes attenuat ed leukocyte ntxeem tau thiab fifibrosis tom qab DOCA kev kho mob.68 Raws li lub paradigm ntawm systemic inflammation nyob rau hauv HFpEF, MR deletion ntawm endothelial hlwb los yog myeloid hlwb pom tau hais tias lub feem ntau striking nyhuv ntawm lub plawv remodeling (Daim duab 2).35–38,54,69
Cov kev sim tshuaj thaum ntxov tau qhia txog cov txiaj ntsig zoo ntawm MRAs hauv cov neeg mob HFpEF.70–72 Yog li, nws tau xav tsis thoob tias spironolactone ua tsis tau zoo los txhim kho cov txiaj ntsig tseem ceeb ntawm kev tuag los ntawm cov hlab plawv, tshem tawm lub plawv nres, lossis mus pw hauv tsev kho mob rau lub plawv tsis ua haujlwm nyob rau theem loj. III Kev Kho Mob Ntawm Cov Mob Ntshav Qab Zib Kev Ua Haujlwm Lub Plawv Tsis Ua Haujlwm nrog Aldosterone Antagonist (TOPCAT) trial.73 Txawm li cas los xij, kev txhawj xeeb loj txog kev kawm coj mus rau cov lus nug txog kev siv tau ntawm txoj kev tshawb no.74,75 Hauv FInerenone hauv reducinG cArdiovascular moRtality thiab mOrbidity hauv ntshav qab zib raum. (FIG ARO-DKD) sim, qhov tsis yog-steroidal MRA finerenone txo qhov tshwm sim ntawm cov kab mob plawv hauv cov neeg mob ntshav qab zib mellitus, 76 pab pawg neeg mob uas muaj kev pheej hmoo siab rau kev tsim HFpEF.60 Qhov tseem ceeb, cov txiaj ntsig zoo ntawm finerenone feem ntau yog tsav los ntawm tus nqi qis dua ntawm kev mus pw hauv tsev kho mob rau lub plawv tsis ua haujlwm, txawm hais tias cov neeg mob uas muaj HFrEF preexisting raug tshem tawm los ntawm kev sim.76 Ob ntxiv theem III kev soj ntsuam kev sim sib piv spironolactone (Spironolactone hauv kev kho mob plawv tsis ua hauj lwm [SPIRIT-HF]; NCT04727073; EudraCT 2017- 000697-11) thiab finerenone (Finerenone Kev sim los tshawb xyuas qhov ua tau zoo thiab kev nyab xeeb zoo dua rau cov placebo hauv cov neeg mob plawv tsis ua hauj lwm [FINEARTS-HF]; NCT04435626) nrog cov placebo hauv cov neeg mob uas muaj lub plawv tsis ua hauj lwm thiab nruab nrab-ntau lossis khaws cia ejection feem tam sim no tsis tu ncua.
Hauv Lub Plawv 'OMics' hauv kev laus (HOMAGE) sim, spironolactone txo cov synthesis thiab nce degradation ntawm hom I collagen, thiab txo cov ntshav siab, sab laug atrial volume, thiab BNP qib hauv cov neeg muaj kev pheej hmoo rau HFpEF.77 Seb puas thaum ntxov MRA kho tuaj yeem ncua. qhov tshwm sim ntawm lub plawv tsis ua hauj lwm nyob rau hauv xws li cov pej xeem tseem yuav txiav txim siab.
Atherosclerosis thiab coronary artery kab mob
Atherosclerosis thiab coronary artery kab mob yog suav hais tias yog cov kab mob inflammatory, 78, thiab lub zog ntawm MR ntawm vascular inflamation tau piav saum toj no qhia txog lub luag haujlwm rau MR hauv lawv cov kab mob pathophysiology. Hauv apolipoprotein E knockout nas qauv, aldosterone infusion exacerbated atherosclerosis txoj kev loj hlob.79 Conversely, MRAs attenuated inflammation thiab tsim ntawm reactive oxygen hom tab sis txhim kho NO bioavailability thiab vascular muaj nuj nqi nyob rau hauv rog qauv.80-83 Aldosterone cuam tshuam rau monoqueflammation nyob rau hauv recruitment thiab plasma. nyob rau hauv nas tsis muaj placental kev loj hlob factor79 los yog intercellular adhesion molecule 1,84 qhia txog kev sib cuam tshuam ntawm endothelial hlwb thiab monocytes hauv cov txheej txheem. Nyob rau hauv vitro, MR txhawb kev qhia ntawm inflammatory molecules nyob rau hauv endothelial hlwb thiab SMCs.39,54,85–87 Nyob rau hauv vivo, MR deletion ntawm endothelial hlwb los yog myeloid hlwb, tab sis tsis yog los ntawm SMCs, ameliorated vascular inflammation nyob rau hauv nas qauv ntawm atherosclerosis.39 -41 Tsis tas li ntawd, stimulation ntawm monocytes nrog aldosterone augmented inflammatory cytokine ntau lawm, nyob ntawm qhov upregulation ntawm fatty acid synthesis pathway.88 Lub cev loj hlob ntawm cov ntaub ntawv ntawm kev ua hauj lwm ntawm myeloid cell MRS nyob rau hauv innate kev tiv thaiv thiab atherosclerosis tau sau tseg los ntawm van der. Heijden et al. (2018).89 Ib cag ntawm lawv cov teebmeem hauv atherosclerosis, MRA kev kho mob thiab MR tshem tawm ntawm SMC lossis myeloid hlwb tau txais txiaj ntsig zoo rau kev kho cov hlab ntsha tom qab kev raug mob, 42,43,90 qhia txog qhov txiaj ntsig zoo ntawm MRAs ntawm postangioplasty restenosis. Txawm hais tias qhov kev sim ua pov thawj tsis txaus ntseeg no, cov ntaub ntawv los ntawm kev sim tshuaj ntsuam xyuas ntawm MRAs hauv atherosclerosis tseem tsis txaus.91 Cov Finerenone tsis ntev los no hauv Kev txo qis raum tsis ua haujlwm thiab kab mob kev loj hlob hauv ntshav qab zib raum kab mob (FIDELIO-DKD) kev sim tau pom rau thawj zaug uas kho nrog MRA tshiab. finerenone tuaj yeem txo qhov tshwm sim ntawm MI hauv cov neeg mob ntshav qab zib mellitus, 92 qhia txog lub luag haujlwm tseem ceeb ntawm MRAs hauv kev tiv thaiv kev mob plawv.
Arterial hypertension
Qhov cuam tshuam ntawm aldosterone thiab MR ntawm arterial hypertension tau raug lees paub rau ntau xyoo lawm. Piv txwv li, aldosterone infusion nce ntshav siab hauv uni nephrectomized nas tau txais kev noj zaub mov muaj ntsev.93,94 Ntxiv rau nws cov teebmeem ntawm Naþ thiab cov kua dej tuav, aldosterone tswj cov ntshav siab ntawm MR hauv cov hlwb sab nraum lub raum.95 Endothelial MR. Kev ua kom ua rau muaj kev tsim cov pa oxygen reactive thiab impaired endothelium-dependent vascular so.44,80 Qhov tseem ceeb, cov teebmeem no tau tshwm sim ntau dua hauv cov poj niam nas, piv nrog cov txiv neej nas.96 MR overexpression ua rau muaj kev nce siab hauv cov ntshav siab.97 Txawm li cas los xij, MR tshem tawm ntawm cov hlwb endothelial tsis hloov ntshav siab ntawm lub hauv paus lossis hauv cov lus teb rau kev txhawb nqa, 36,44,45,69 qhia tias MR hauv cov hlwb endothelial ntawm lub cev qhia theem yog siv rau kev tswj ntshav siab. Nyob rau hauv sib piv, ntau cov kev tshawb fawb taw tes rau MRS nyob rau hauv SMCs raws li ib tug tseem ceeb determinant ntawm vascular txhav thiab kub siab, tshwj xeeb tshaj yog nyob rau hauv cov nas muaj hnub nyoog (Daim duab 2).46–48,98 Nws tau pom tias MR ntawm kev tawm tsam ntawm miR-155 txhim kho kev nthuav qhia thiab kev ua ntawm L-type Ca2þ channels hauv SMCs, ua rau muaj kev nce hauv vascular tone.46,47 Angiotensin II-induced hypertension thiab tom qab raug mob ntawm lub cev tau raug cuam tshuam los ntawm MR tshem tawm ntawm T cells.49 Hais txog lub luag haujlwm ntawm MR hauv cov hlwb myeloid, ib nrab qhov tsis sib haum xeeb tau tshaj tawm txog cov ntshav siab teb rau DOC / ntsev hy pertension37 lossis angiotensin II / L-NAME.29,38 Spironolactone tau ua pov thawj zoo rau cov neeg mob ntshav siab hauv ntau qhov kev sim tshuaj thiab tam sim no pom zoo rau cov neeg mob. Sustained hypertension txawm tias triple therapy.99,100 Cov nonsteroidal MRA esaxerenone muaj txiaj ntsig zoo ib yam li eplerenone hauv kev txo cov ntshav siab thiab tam sim no tau pom zoo hauv Nyij Pooj rau kev kho mob hyperte tseem ceeb. nsion.101,102 Hauv kev sim theem 2b tsis ntev los no, qhov nonsteroidal MRA KBP-5074 tuaj yeem txo cov ntshav siab hauv cov neeg mob uas muaj kab mob raum ntev thiab tsis tswj ntshav siab txawm tias muaj kev kho mob nrog rau renin-angiotensin system inhibitor.103 Hauv qhov sib piv, hauv cov neeg mob uas muaj kab mob raum ntev thiab tswj tau cov ntshav siab zoo, fininerenone tsuas muaj qhov cuam tshuam me me ntxiv rau cov ntshav siab.76,104
PH thiab lub plawv tsis ua haujlwm
Kev nce qib plasma aldosterone tau pom nyob rau hauv cov neeg mob nrog PH thiab hauv cov nas tom qab raug mob hypoxia, 50,105,106 hinting ntawm lub luag haujlwm rau MR hauv pulmonary vascular remodeling. Qhov tseeb, aldosterone stimulation induces PH phenotypes hauv vivo thiab hauv kab lis kev cai SMCs lossis endothelial hlwb hauv vitro.50,107-109 MRAs txhim kho vascular remodeling thiab txoj cai ventricular muaj nuj nqi cuam tshuam los ntawm kev mob hypoxia lossis monocrotaline hauv nas thiab nas. nyob rau hauv ib tug pulmonary artery banding qauv, implying hais tias cov txiaj ntsig ntawm MRAs ntawm txoj cai ventricular muaj peev xwm yuav piav qhia ncaj qha los ntawm qhov txo qis tom qab load.110 Kev sim kev tshawb fawb siv cov nas nrog cell-type-specific MR deletion qhia tias qhov cuam tshuam ntawm aldosterone ntawm pulmonary vasculature. yog kho los ntawm MR nyob rau hauv endothelial hlwb es tsis yog SMCs, fibroblasts, los yog macrophages (Daim duab 2).50 Gene qhia kev soj ntsuam thiab nyob rau hauv vitro kev tshawb fawb taw tes ntawm kev sib cuam tshuam ntawm endothelial hlwb thiab lwm yam cell nyob rau hauv tus txheej txheem, nrog rau cov endothelin{13 } } signaling pathway thiab paracrine crosstalk ntawm exosomes.50,108,109,111 A post hoc tsom xam los ntawm Ambrisentan rau Kev Kho Mob ntawm Pulmonary Arterial Hypertension (ARIES) 1 thiab 2 qhov kev sim qhia pom tias muaj txiaj ntsig zoo ntawm spironolactone thaum ntxiv rau endothelin -1 receptor antagonist ambrisentan nyob rau hauv cov neeg mob nrog PH.112 Ib qho kev tshwm sim randomized theem 2 kev soj ntsuam ntawm MRA siv hauv PH yog tam sim no. (NCT01712620).
Tej zaum cov lus qhia yav tom ntej Kev paub txog kev cuam tshuam MR hauv cov kab mob plawv txuas ntxiv nthuav dav, taw qhia txog qhov muaj peev xwm tshiab rau MRAs. Qhov muaj cov tshiab, nonsteroidal MRAs tuaj yeem nthuav dav ntxiv ntawm cov cim qhia thiab ua rau kev siv tshuaj kho mob ntawm MRAs hauv cov neeg mob uas muaj kev pheej hmoo siab.4 Cov ntaub ntawv kho mob ua ntej thiab thaum ntxov qhia tias MRAs tuaj yeem ua tau zoo hauv kev tiv thaiv cov tshuaj tua kab mob uas ua rau mob plawv, muaj feem cuam tshuam. ntawm cov tshuaj tiv thaiv kab mob ua rau LV tsis ua haujlwm, hauv cov poj niam cov neeg mob.51,113,114 Tsis tas li ntawd, cov pov thawj loj hlob qhia tau tias kev ua kom MR ua rau muaj kev cuam tshuam tsis zoo ntawm cov ventricles tab sis kuj ntawm atria. Cov neeg mob uas muaj thawj aldosteronism muaj kev pheej hmoo siab dua ntawm kev txhim kho atrial fibrillation piv nrog cov neeg mob uas muaj qhov tseem ceeb kub siab.115 Intriguingly, atrial fibrosis induced los ntawm transforming loj hlob factor b yog attenuated los ntawm MR deletion nyob rau hauv osteoblasts (Daim duab 2).52 Nyob rau hauv ntau yam kev sim qauv, MRAs txo. atrial fifibrosis thiab yog li lub nra ntawm atrial arrhythmia, 116-118 qhia txog qhov txiaj ntsig zoo ntawm MRAs hauv cov neeg mob atrial fibrillation. Nyob rau hauv txoj kab nrog qhov muaj peev xwm no, ib qho kev tshuaj ntsuam meta-kev soj ntsuam ntawm kev sim tshuaj tau qhia txog qhov txo qis ntawm qhov tshwm sim ntawm atrial fibrillation hauv MRA-kho cov neeg mob, piv nrog cov pab pawg tswj.119
Mitral regurgitation yog ib hom kab mob plawv feem ntau cuam tshuam nrog cov txheej txheem deterioration thiab cuam tshuam extracellular matrix ntawm mitral valve leaflets.120 Cov pov thawj tsis ntev los no qhia tias aldosterone, los ntawm kev ua kom MR, tsav cov proteoglycan ntau lawm los ntawm interstitial hlwb thiab endothelial-rau-mesenchymal hloov nyob rau hauv. mitral li qub.53 Hauv nas, kev kho MRA lossis MR tshem tawm hauv cov hlwb endothelial attenuated mitral valve remodeling.53 Cov nyhuv no tau nrog los ntawm kev txo qis ntawm cov cim fibrotic hauv LV cov ntaub so ntswg hauv cov nas uas kho nrog spironolactone.121 Txawm tias tam sim no txwv rau kev cuam tshuam lossis kev kho phais, MRAs tuaj yeem sawv cev rau txoj kev kho tshiab rau mitral regurgitation.6,120
Cov lus xaus
Cov ntaub ntawv pov thawj tau sau los ntawm ntau qhov kev sim ua kom pom tias Mrs hauv plawv myocytes, endothelial cells, SMCs, myeloid cells, T cells, thiab osteoblasts muaj kev cuam tshuam ncaj qha rau lub plawv tsis ua haujlwm thiab lwm yam kab mob plawv. Nyob ntawm seb hom kab mob los yog kev txhawb nqa, ntau hom xov tooj ntawm tes muaj MRS nrog cov haujlwm sib txawv uas ua rau muaj txiaj ntsig zoo ntawm kev mob plab thiab fifibrosis tom qab ua kom tiav. Cov kev pom muaj nyob rau hauv qhov kev tshuaj xyuas no yuav muab lub hauv paus rau kev txhim kho ntxiv thiab kev ntsuam xyuas ntawm classical thiab tshiab MRAs rau cov kab mob plawv ntxiv.
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