Abstract
The differentiation of cardiac fibroblasts to myofibroblasts is considered to be a critical step in activation and progression of cardiac fibrosis in heart disease. TGF-β is one of the key cytokines that promotes transition of fibroblasts to myofibroblasts. Dedifferentiation of formed myofibroblasts or reversal of formed myofibroblasts to fibroblasts remains incompletely understood. Prostaglandin E2 (PGE2) has been shown to dedifferentiate human lung myofibroblasts. The role of activation of the COX-2/PGE2 pathway in dedifferentiation of cardiac myofibroblasts remains unknown. Here, we show that phorbol 12-myristate 13-acetate (PMA) but not PGE2 induces dedifferentiation of de novo adult human cardiac myofibroblasts stimulated by TGF-β1 from human cardiac fibroblasts as evidenced by reduced expression of α-smooth muscle actin (α-SMA). PMA remarkably increased endogenous levels of PGE2 in human cardiac myofibroblasts. Pretreatment of myofibroblasts with NS-398, a selective COX-2 inhibitor, and PF-04418948, a selective PGE2 receptor type 2 (EP2) antagonist, had no effect on expression of α-SMA nor abolished the dedifferentiation induced by PMA. Our results indicated that endogenous and exogenous PGE2 has no effects on dedifferentiation of cardiac myofibroblasts. PMA-induced dedifferentiation of cardiac myofibroblast is independent of activation of COX-2 and PGE2 pathway. The mechanism in PMA-induced reversal of cardiac myofibroblasts needs to be explored further.
Highlights
Cardiac fibrosis is the consequence of production and secretion of excessive extracellular matrix (ECM) proteins, such as: collagens, fibronectin, and elastin, etc., in myocardium
Myofibroblasts differentiated from fibroblasts secrete collagens and other ECM proteins that limit cardiac functions and underlie the basis of cardiac fibrosis because of myocardial infarction or other non-ischemic risk factors, such as: diabetes, hypertension, or valvular diseases [5]
phorbol 12-myristate 13-acetate (PMA) sioennhinanacreespaocrtitveirtyasosfaCyO[2X0-]2. and stimulates production of Prostaglandin E2 (PGE2) in neonatal rat cardiac myTohceyteefsfevcita oPfKCCOaXn-d2/MPGAEP2Kpaacthtiwvaatiyonon[1d9e].diPffMerAenintidauticoens oNfKh-uκmB-adnepceanrddeianct mgeynoefibroblaesxtpsrreesmsioaninineda urenpkonrtoewr ans.sIany t[h20e].present study, we investigated this by utilizing de novo myofibTrohebleafsfetcstdoifffCeOreXn-2ti/aPteGdE2frpoamthhwuamy oanndceadridffiearcenfitbiartoiobnlaosftshuwmitahnTcaGrdFi-aβc1m(Fyiogfiubrreob1-)
Summary
Cardiac fibrosis is the consequence of production and secretion of excessive extracellular matrix (ECM) proteins, such as: collagens, fibronectin, and elastin, etc., in myocardium. Myofibroblasts differentiated from fibroblasts secrete collagens and other ECM proteins that limit cardiac functions and underlie the basis of cardiac fibrosis because of myocardial infarction or other non-ischemic risk factors, such as: diabetes, hypertension, or valvular diseases [5]. Strategies to reverse myofibroblasts to fibroblasts or dedifferentiation of formed myofibroblasts, which is a process to revert to an inactive of cardiac functional change and symptoms. Accumulating evidence indicates that myofibroblasts have capacity forpdheendoitfyfepreecnhtaiaraticotenr,isaticporof cmeysosfiwbrhoibclhasitspdreecfuinrseodr caesllsth, teo lroessoslvoef fiαb-SroMsiAs h, atvheeehmaelrlgmeadrk for myroecfeibnrtloybalansdtsha[v9e].cPlirnoicmalorteiloenvaonfcem[y10o–f1ib2]r.oblast dedifferentiation may represent a novel mechanMisymofifborrobfilbasrtosswiserestoraludittiioonna[l1ly0–c1o5n]s.idered to be terminally differentiated cells and weSreomnoet rmevoelrescibullee.sAhcacuvme ubleaetinngdeevmidoennscteraintdedicattoesdtheadtifmfeyroefinbtiraotbelamstsyhoafivbercoabplaacsittsy. Both profosrtadgeldainffdeirnenEti2a(tPioGn,Ea2)parnocdesfsibwrohbiclhasits gdreofiwnethd afasctthoer l2os(sFoGfFα2-)SMarAe ,mthoelehcaulllmesartkhafot rdediffermenytoiafitberolublnagstsm[9y]o.
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