title: 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside protects murine hearts against ischemia/reperfusion injury by activating Notch1/Hes1 signaling and attenuating endoplasmic reticulum stress.
abstract: 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is a water-soluble active component extracted from Polygonum multiflorum Thunb. A number of studies demonstrate that TSG exerts cardioprotective effects. Since endoplasmic reticulum (ER) stress plays a key role in myocardial ischemia/reperfusion (MI/R)-induced cell apoptosis, we sought to determine whether modulation of the ER stress during MI/R injury was involved in the cardioprotective action of TSG. Male mice were treated with TSG (60 mg·kg-1·d-1, ig) for 2 weeks and then were subjected to MI/R surgery. Pre-administration of TSG significantly improved post-operative cardiac function, and suppressed MI/R-induced myocardial apoptosis, evidenced by the reduction in the myocardial apoptotic index, serum levels of LDH and CK after 6 h of reperfusion. TSG (0.1-1000 μmol/L) did not affect the viability of cultured H9c2 cardiomyoblasts in vitro, but pretreatment with TSG dose-dependently decreased simulated ischemia/reperfusion (SIR)-induced cell apoptosis. Furthermore, both in vivo and in vitro studies revealed that TSG treatment activated the Notch1/Hes1 signaling pathway and suppressed ER stress, as evidenced by increasing Notch1, Notch1 intracellular domain (NICD), Hes1, and Bcl-2 expression levels and by decreasing p-PERK/PERK ratio, p-eIF2α/eIF2α ratio, and ATF4, CHOP, Bax, and caspase-3 expression levels. Moreover, the protective effects conferred by TSG on SIR-treated H9c2 cardiomyoblasts were abolished by co-administration of DAPT (the Notch1 signaling inhibitor). In summary, TSG ameliorates MI/R injury in vivo and in vitro by activating the Notch1/Hes1 signaling pathway and attenuating ER stress-induced apoptosis.
authors.affiliation: Institute of Material Medical, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.|Department of Cardiovascular Surgery, General Hospital of Shenyang Military Area Command, Shenyang 110016, China.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Yu
authors.affiliation: Institute of Material Medical, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Institute of Material Medical, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xuan-Xuan
authors.initials: XX
authors.lastname: Zhou
authors.affiliation: Institute of Material Medical, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Institute of Material Medical, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Song
authors.affiliation: Institute of Material Medical, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Meng-En
authors.initials: ME
authors.lastname: Zhai
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Bu-Ying
authors.initials: BY
authors.lastname: Li
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zhen-Xiao
authors.initials: ZX
authors.lastname: Jin
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Wei-Xun
authors.initials: WX
authors.lastname: Duan
authors.affiliation: Institute of Material Medical, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Si-Wang
authors.initials: SW
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D005960:Glucosides / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008810:Mice, Inbred C57BL; D032386:Myoblasts, Cardiac / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use; D000072056:Transcription Factor HES-1 / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D005960:Glucosides; C489734:Hes1 protein, mouse; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D013267:Stilbenes; D000072056:Transcription Factor HES-1; C093026:2,3,5,4'-tetrahydroxystilbene 2-O-glucopyranoside