Metformin and tanshinone llA as ethnodrugs protect heart against injury by inhibiting microRNA-1
- Author:
Lei JIAO
1
;
Ying ZHANG
;
Xue LIU
;
Lu ZHANG
;
Hong-Li SHAN
;
Yong ZHANG
;
Bao-Feng YANG
Author Information
1. Department of Pharmacology(the State-Province Key Laboratories of Biomedicine Pharmaceutics of China Key Laboratory of Cardiovascular Research
- Keywords:
metformin;
tanshinone IIA;
microRNA-1;
endoplasmic reticulum stress
- From:
Chinese Journal of Pharmacology and Toxicology
2018;32(4):290-290
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE To explore the protection mechanism of metformin and tanshinone IIA on myocardial injury. METHODS The cultured neonatal rat ventricular cells (NRVCs) were exposed to 100 μmol·L-1H2O2to simulate the in vitro model of ischemia-reperfusion injury.MTT,TUNEL and Viability/Cytotoxicity Assay were used to evaluate the effect of metformin on the viability of cardiomyocytes after treated with H2O2. The target of miR-1 was verified by Dual luciferase reporter assay. ChIP analyses was adopted to reveal the relationship between C/EBP β and miR-1.Tanshinone IIA was administrated daily for 7 d before ligation of the left anterior descending artery (LAD) and lasted for 3 months after LAD.Whole-cell patch-clamp techniques were used to measure the inward rectifying K+current(IK1)in rat isolated ventricular myocytes.GRP94,p-AMPKα,C/EBP β,CHOP,Caspase-3,Kir2.1,p38 MAPK, Cx43, MEF2 and SRF levels were analyzed by Western blot and miR-1 level was quantified by Real-time PCR.RESULTS The expression of miR-1 was significantly increased in NRVCs exposed to H2O2 in vitro. miR-1 was shown to target the 3′-untranslated region (UTR) of GRP94, which results in the accumulation of un/misfolded proteins,leading to the endoplasmic reticulum(ER)stress.C/EBP β directly induces the upregulation of miR-1 by binding to its promoter.Furthermore,metformin,a direct allosteric AMPK activator, significantly reduces C/EBP β and miR-1 levels comparing with control group. Similarly, tanshinone IIA decreased the incidence of arrhythmias and relieved ischemia-induced injury.Moreover, tanshinone IIA depressed the elevated miR-1 level and inhibited the activation of p38 MAPK and heart special transcription factors SRF and MEF2 in ischemic cardiomyocytes. CONCLUSION Metformin protects cardiomyocytes against H2O2damage through AMPK/C/EBPβ/miR-1/GRP94 pathway.Tanshi-none IIA play a role in protection cardiomyocytes from ischemic injury based on inhibiting miR-1 expres-sion through p38 MAPK signal pathway.
