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Yang Yang - One of the best experts on this subject based on the ideXlab platform.

  • melatonin protects diabetic heart against ischemia reperfusion injury role of membrane receptor dependent cgmp pkg activation
    Biochimica et Biophysica Acta, 2018
    Co-Authors: Xue Dong, Yang Yang, Yong Zhang, Xiaodong Xue, Jian Zhang, Xiong Xiao, Jinsong Han, Yu Liu, Huishan Wang
    Abstract:

    It has been demonstrated that the anti-oxidative and cardioprotective effects of melatonin are, at least in part, mediated by its membrane receptors. However, the direct downstream signaling remains unknown. We previously found that melatonin ameliorated myocardial ischemia-reperfusion (MI/R) injury in diabetic animals, although the underlying mechanisms are also incompletely understood. This study was designed to determine the role of melatonin membrane receptors in melatonin's cardioprotective actions against diabetic MI/R injury with a focus on cGMP and its downstream effector PKG. Streptozotocin-induced diabetic Sprague-Dawley rats and high-glucose medium-incubated H9c2 cardiomyoblasts were utilized to determine the effects of melatonin against MI/R injury. Melatonin treatment preserved cardiac function and reduced oxidative damage and apoptosis. Additionally, melatonin increased intracellular cGMP level, PKGIα expression, p-VASP/VASP ratio and further modulated myocardial Nrf-2-HO-1 and MAPK signaling. However, these effects were blunted by KT5823 (a selective inhibitor of PKG) or PKGIα siRNA except that intracellular cGMP level did not changed significantly. Additionally, our in vitro study showed that Luzindole (a nonselective melatonin membrane receptor antagonist) or 4P-PDOT (a selective MT2 receptor antagonist) not only blocked the cytoprotective effect of melatonin, but also attenuated the stimulatory effect of melatonin on cGMP-PKGIα signaling and its modulatory effect on Nrf-2-HO-1 and MAPK signaling. This study showed that melatonin ameliorated diabetic MI/R injury by modulating Nrf-2-HO-1 and MAPK signaling, thus reducing myocardial apoptosis and oxidative stress and preserving cardiac function. Importantly, melatonin membrane receptors (especially MT2 receptor)-dependent cGMP-PKGIα signaling played a critical role in this process.

  • melatonin rescues cardiac thioredoxin system during ischemia reperfusion injury in acute hyperglycemic state by restoring notch1 hes1 akt signaling in a membrane receptor dependent manner
    Journal of Pineal Research, 2017
    Co-Authors: Liming Yu, Yinli Xu, Zhi Li, Guolong Zhao, Yang Yang, Huishan Wang
    Abstract:

    Stress hyperglycemia is commonly observed in patients suffering from ischemic heart disease. It not only worsens cardiovascular prognosis but also attenuates the efficacies of various cardioprotective agents. This study aimed to investigate the protective effect of melatonin against myocardial ischemia-reperfusion (MI/R) injury in acute hyperglycemic state with a focus on Notch1/Hes1/Akt signaling and intracellular thioredoxin (Trx) system. Sprague-Dawley rats were subjected to MI/R surgery and high glucose (HG, 500 g/L) infusion (4 ml/kg/h) to induce temporary hyperglycemia. Rats were treated with or without melatonin (10 mg/kg/d) during the operation. Furthermore, HG (33mM) incubated H9c2 cardiomyoblasts were treated in the presence or absence of Luzindole (a competitive melatonin receptor antagonist), DAPT (a γ-Secretase inhibitor), LY294002 (a PI3-kinase/Akt inhibitor) or thioredoxin-interacting protein (Txnip) adenoviral vectors. We found that acute hyperglycemia aggravated MI/R injury by suppressing Notch1/Hes1/Akt signaling and intracellular Trx activity. Melatonin treatment effectively ameliorated MI/R injury by reducing infarct size, myocardial apoptosis and oxidative stress. Moreover, melatonin also markedly enhanced Notch1/Hes1/Akt signaling and rescued intracellular Trx system by up-regulating Notch1, N1ICD, Hes1 and p-Akt expressions, increasing Trx activity and down-regulated Txnip expression. However, these effects were blunted by Luzindole, DAPT or LY294002. Additionally, Txnip overexpression not only decreased Trx activity, but also attenuated the cytoprotective effect of melatonin. We conclude that impaired Notch1 signaling aggravates MI/R injury in acute hyperglycemic state. Melatonin rescues Trx system by reducing Txnip expression via Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner. Its role as a prophylactic/therapeutic drug deserves further clinical study. This article is protected by copyright. All rights reserved.

  • membrane receptor dependent notch1 hes1 activation by melatonin protects against myocardial ischemia reperfusion injury in vivo and in vitro studies
    Journal of Pineal Research, 2015
    Co-Authors: Liming Yu, Mengen Zhai, Dinghua Yi, Hongliang Liang, Wensheng Chen, Zhihong Lu, Guolong Zhao, Jian Yang, Yang Yang, Xiaowu Wang
    Abstract:

    Melatonin confers profound protective effect against myocardial ischemia-reperfusion injury (MI/RI). Activation of Notch1/Hairy and enhancer of split 1 (Hes1) signaling also ameliorates MI/RI. We hypothesize that melatonin attenuates MI/RI-induced oxidative damage by activating Notch1/Hes1 signaling pathway with phosphatase and tensin homolog deleted on chromosome 10 (Pten)/Akt acting as the downstream signaling pathway in a melatonin membrane receptor-dependent manner. Male Sprague Dawley rats were treated with melatonin (10 mg/kg/day) for 4 wk and then subjected to MI/R surgery. Melatonin significantly improved cardiac function and decreased myocardial apoptosis and oxidative damage. Furthermore, in cultured H9C2 cardiomyocytes, melatonin (100 μmol/L) attenuated simulated ischemia-reperfusion (SIR)-induced myocardial apoptosis and oxidative damage. Both in vivo and in vitro study demonstrated that melatonin treatment increased Notch1, Notch1 intracellular domain (NICD), Hes1, Bcl-2 expressions, and p-Akt/Akt ratio and decreased Pten, Bax, and caspase-3 expressions. However, these protective effects conferred by melatonin were blocked by DAPT (the specific inhibitor of Notch1 signaling), Luzindole (the antagonist of melatonin membrane receptors), Notch1 siRNA, or Hes1 siRNA administration. In summary, our study demonstrates that melatonin treatment protects against MI/RI by modulating Notch1/Hes1 signaling in a receptor-dependent manner and Pten/Akt signaling pathways are key downstream mediators.

  • melatonin receptor mediated protection against myocardial ischemia reperfusion injury role of sirt1
    Journal of Pineal Research, 2014
    Co-Authors: Liming Yu, Mengen Zhai, Xiaowu Wang, Yang Yang, Liang Cheng, Haifeng Zhang, Qiang Meng, Yu Zhang, Shiqiang Yu, Weixun Duan
    Abstract:

    Abstract Melatonin confers cardioprotective effect against myocardial ischemia/reperfusion (MI/R) injury by reducing oxidative stress. Activation of silent information regulator 1 (SIRT1) signaling also reduces MI/R injury. We hypothesize that melatonin may protect against MI/R injury by activating SIRT1 signaling. This study investigated the protective effect of melatonin treatment on MI/R heart and elucidated its potential mechanisms. Rats were exposed to melatonin treatment in the presence or the absence of the melatonin receptor antagonist Luzindole or SIRT1 inhibitor EX527 and then subjected to MI/R operation. Melatonin conferred a cardioprotective effect by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase release, upregulating SIRT1, Bcl-2 expression and downregulating Bax, caspase-3 and cleaved caspase-3 expression. Melatonin treatment also resulted in reduced myocardium superoxide generation, gp91(phox) expression, malondialdehyde level, and increased myocardium superoxide dismutase (SOD) level, which indicate that the MI/R-induced oxidative stress was significantly attenuated. However, these protective effects were blocked by EX527 or Luzindole, indicating that SIRT1 signaling and melatonin receptor may be specifically involved in these effects. In summary, our results demonstrate that melatonin treatment attenuates MI/R injury by reducing oxidative stress damage via activation of SIRT1 signaling in a receptor-dependent manner.

Margarita L. Dubocovich - One of the best experts on this subject based on the ideXlab platform.

  • effects of the melatonin receptor antagonist mt2 inverse agonist mt1 Luzindole on re entrainment of wheel running activity and spontaneous homecage behaviors in c3h hen mice
    The FASEB Journal, 2012
    Co-Authors: E B Adamahbiassi, Iwona Stepien, Randall L Hudson, Margarita L. Dubocovich
    Abstract:

    Activation of MT1 receptors by melatonin accelerates the re-entrainment of circadian rhythms of wheel running activity after an abrupt advance of the dark cycle (Dubocovich et al., 2005). Here, we ...

  • the antidepressant like effect of the melatonin receptor ligand Luzindole in mice during forced swimming requires expression of mt2 but not mt1 melatonin receptors
    Journal of Pineal Research, 2005
    Co-Authors: I C Sumaya, Monica I Masana, Margarita L. Dubocovich
    Abstract:

    We previously reported an antidepressant-like effect in C3H/HeN mice during the forced swimming test (FST) following treatment with the MT 1 /MT 2 melatonin receptor ligand, Luzindole. This study investigated the role melatonin receptors (MT 1 and/or MT 2 ) may play in the effect of Luzindole in the FST using C3H/HeN mice with a genetic deletion of either MT 1 (MTIKO) or MT 2 (MT 2 KO) melatonin receptors. In the light phase (ZT 9-11), Luzindole (30 mg/kg, i.p.) significantly decreased immobility during swimming in both wild type (WT) (135.6 ± 25.3 s, n = 7) and MTIKO (132.6 ± 13.3 s, n = 8) as compared with vehicle-treated mice (WT: 207.1 ± 6.0 s, n = 7; MT 1 KO: 209.5 ± 6.2 s, n = 8) (P < 0.001). In the dark phase (ZT 20-22), Luzindole also decreased time of immobility in both WT (89.5 ± 13.9 s, n = 8) and MT 1 KO (66.5 ± 6.4 s, n = 8) mice as compared with the vehicle treated (WT: 193.8 ± 3.5, n = 6; MT 1 KO: 176.6 ± 6.2 s, n = 8) (P < 0.001). Genetic disruption of the MT 1 gene did not alter the diurnal rhythm of serum melatonin in MTIKO mice (ZT 9-11: 1.3 ± 0.6 pg/mL, n = 7; ZT 20-22: 10.3 ± 1.1 pg/mL, n = 8) as compared with WT (ZT 9-11: 1.4 ± 0.7 pg/mL; ZT 20-22: 10.6 pg/mL). Swimming did not alter the serum melatonin diurnal rhythm in WT and MTIKO mice. Decreases in immobility of WT and MTIKO mice by Luzindole treatment were not affected by gender or age (3 months versus 8 months). In contrast, Luzindole did not decrease immobility during the FST in MT 2 KO mice. We conclude that the antidepressant-like effect of Luzindole may be mediated through blockade of MT 2 rather than MT 1 melatonin receptors.

  • functional melatonin receptors in rat ovaries at various stages of the estrous cycle
    Journal of Pharmacology and Experimental Therapeutics, 2003
    Co-Authors: Jose M Soares, Monica I Masana, Cagatay Ersahin, Margarita L. Dubocovich
    Abstract:

    This study investigated the receptor mechanism(s) by which the hormone melatonin directly affects ovarian function. Expression of MT1 and MT2 melatonin receptor mRNA was detected in the rat ovaries both by reverse transcriptase-polymerase chain reaction and in situ hybridization with digoxigenin-labeled oligoprobes. Specific 2-[125I]iodomelatonin binding was significantly higher in ovarian tissue from animals sacrificed during proestrus than in metestrus, suggesting regulation of melatonin receptors by estrogens. Additionally, basal and melatonin-mediated stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding to ovarian sections was higher in proestrus compared with metestrus. During proestrus, both Luzindole (0.1 microM) and 4-phenyl-2-propionamidotetraline (4P-PDOT) (0.1 microM), acting as inverse agonists, inhibited basal [35S]GTPgammaS binding to ovarian sections, suggesting the presence of MT1 constitutively active melatonin receptors. In primary cultures of ovarian granulosa cells, melatonin inhibited forskolin-stimulated cAMP accumulation through activation of Gi-coupled melatonin receptors. This inhibition was blocked by both, Luzindole, and 4P-PDOT, acting as competitive receptor antagonists. Exposure of granulosa cells in culture to 17beta-estradiol seems to alter the state of melatonin receptor coupling. Indeed, the efficacy of 4P-PDOT on forskolin-stimulated cAMP formation was reversed from an MT2 partial agonist in vehicle-treated cells to that of an MT1 inverse agonist in 17beta-estradiol (0.1 microM)-treated granulosa cells. We conclude that MT1 and MT2 melatonin receptors expressed in antral follicles and corpus luteum may affect steroidogenesis through cAMP-mediated signaling. These results underscore the implications of the levels of ovarian estrogen when melatonin receptor ligands are used as therapeutic agents.

  • activation of mt2 melatonin receptors in rat suprachiasmatic nucleus phase advances the circadian clock
    American Journal of Physiology-cell Physiology, 2001
    Co-Authors: Amanda E Hunt, Walid M Alghoul, Martha U Gillette, Margarita L. Dubocovich
    Abstract:

    The aim of this study was to identify the melatonin receptor type(s) (MT1 or MT2) mediating circadian clock resetting by melatonin in the mammalian suprachiasmatic nucleus (SCN). Quantitative receptor autoradiography with 2-[125I]iodomelatonin and in situ hybridization histochemistry, with either 33P- or digoxigenin-labeled antisense MT1 and MT2 melatonin receptor mRNA oligonucleotide probes, revealed specific expression of both melatonin receptor types in the SCN of inbred Long-Evans rats. The melatonin receptor type mediating phase advances of the circadian rhythm of neuronal firing rate in the SCN slice was assessed using competitive melatonin receptor antagonists, the MT1/MT2nonselective Luzindole and the MT2-selective 4-phenyl-2-propionamidotetraline (4P-PDOT). Luzindole and 4P-PDOT (1 nM-1 μM) did not affect circadian phase on their own; however, they blocked both the phase advances (∼4 h) in the neuronal firing rate induced by melatonin (3 pM) at temporally distinct times of day [i.e., subjective d...

  • selective mt2 melatonin receptor antagonists block melatonin mediated phase advances of circadian rhythms
    The FASEB Journal, 1998
    Co-Authors: Margarita L. Dubocovich, Kenneth Yun, Walid M Alghoul, Susan Benloucif, Monica I Masana
    Abstract:

    This study demonstrates the involvement of the MT2 (Mel1b) melatonin receptor in mediating phase advances of circadian activity rhythms by melatonin. In situ hybridization histochemistry with digoxigenin-labeled oligonucleotide probes revealed for the first time the expression of mt1 and MT2 melatonin receptor mRNA within the suprachiasmatic nucleus of the C3H/HeN mouse. Melatonin (0.9 to 30 μg/mouse, s.c.) administration during 3 days at the end of the subjective day (CT 10) to C3H/HeN mice kept in constant dark phase advanced circadian rhythms of wheel running activity in a dose-dependent manner [EC50=0.72 μg/mouse; 0.98±0.08 h (n=15) maximal advance at 9 μg/mouse]. Neither the selective MT2 melatonin receptor antagonists 4P-ADOT and 4P-PDOT (90 μ/mouse, s.c.) nor Luzindole (300 μg/mouse, s.c.), which shows 25-fold higher affinity for the MT2 than the mt1 subtype, affected the phase of circadian activity rhythms when given alone at CT 10. All three antagonists, however, shifted to the right the dose-res...

Liming Yu - One of the best experts on this subject based on the ideXlab platform.

  • melatonin rescues cardiac thioredoxin system during ischemia reperfusion injury in acute hyperglycemic state by restoring notch1 hes1 akt signaling in a membrane receptor dependent manner
    Journal of Pineal Research, 2017
    Co-Authors: Liming Yu, Yinli Xu, Zhi Li, Guolong Zhao, Yang Yang, Huishan Wang
    Abstract:

    Stress hyperglycemia is commonly observed in patients suffering from ischemic heart disease. It not only worsens cardiovascular prognosis but also attenuates the efficacies of various cardioprotective agents. This study aimed to investigate the protective effect of melatonin against myocardial ischemia-reperfusion (MI/R) injury in acute hyperglycemic state with a focus on Notch1/Hes1/Akt signaling and intracellular thioredoxin (Trx) system. Sprague-Dawley rats were subjected to MI/R surgery and high glucose (HG, 500 g/L) infusion (4 ml/kg/h) to induce temporary hyperglycemia. Rats were treated with or without melatonin (10 mg/kg/d) during the operation. Furthermore, HG (33mM) incubated H9c2 cardiomyoblasts were treated in the presence or absence of Luzindole (a competitive melatonin receptor antagonist), DAPT (a γ-Secretase inhibitor), LY294002 (a PI3-kinase/Akt inhibitor) or thioredoxin-interacting protein (Txnip) adenoviral vectors. We found that acute hyperglycemia aggravated MI/R injury by suppressing Notch1/Hes1/Akt signaling and intracellular Trx activity. Melatonin treatment effectively ameliorated MI/R injury by reducing infarct size, myocardial apoptosis and oxidative stress. Moreover, melatonin also markedly enhanced Notch1/Hes1/Akt signaling and rescued intracellular Trx system by up-regulating Notch1, N1ICD, Hes1 and p-Akt expressions, increasing Trx activity and down-regulated Txnip expression. However, these effects were blunted by Luzindole, DAPT or LY294002. Additionally, Txnip overexpression not only decreased Trx activity, but also attenuated the cytoprotective effect of melatonin. We conclude that impaired Notch1 signaling aggravates MI/R injury in acute hyperglycemic state. Melatonin rescues Trx system by reducing Txnip expression via Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner. Its role as a prophylactic/therapeutic drug deserves further clinical study. This article is protected by copyright. All rights reserved.

  • membrane receptor dependent notch1 hes1 activation by melatonin protects against myocardial ischemia reperfusion injury in vivo and in vitro studies
    Journal of Pineal Research, 2015
    Co-Authors: Liming Yu, Mengen Zhai, Dinghua Yi, Hongliang Liang, Wensheng Chen, Zhihong Lu, Guolong Zhao, Jian Yang, Yang Yang, Xiaowu Wang
    Abstract:

    Melatonin confers profound protective effect against myocardial ischemia-reperfusion injury (MI/RI). Activation of Notch1/Hairy and enhancer of split 1 (Hes1) signaling also ameliorates MI/RI. We hypothesize that melatonin attenuates MI/RI-induced oxidative damage by activating Notch1/Hes1 signaling pathway with phosphatase and tensin homolog deleted on chromosome 10 (Pten)/Akt acting as the downstream signaling pathway in a melatonin membrane receptor-dependent manner. Male Sprague Dawley rats were treated with melatonin (10 mg/kg/day) for 4 wk and then subjected to MI/R surgery. Melatonin significantly improved cardiac function and decreased myocardial apoptosis and oxidative damage. Furthermore, in cultured H9C2 cardiomyocytes, melatonin (100 μmol/L) attenuated simulated ischemia-reperfusion (SIR)-induced myocardial apoptosis and oxidative damage. Both in vivo and in vitro study demonstrated that melatonin treatment increased Notch1, Notch1 intracellular domain (NICD), Hes1, Bcl-2 expressions, and p-Akt/Akt ratio and decreased Pten, Bax, and caspase-3 expressions. However, these protective effects conferred by melatonin were blocked by DAPT (the specific inhibitor of Notch1 signaling), Luzindole (the antagonist of melatonin membrane receptors), Notch1 siRNA, or Hes1 siRNA administration. In summary, our study demonstrates that melatonin treatment protects against MI/RI by modulating Notch1/Hes1 signaling in a receptor-dependent manner and Pten/Akt signaling pathways are key downstream mediators.

  • melatonin receptor mediated protection against myocardial ischemia reperfusion injury role of sirt1
    Journal of Pineal Research, 2014
    Co-Authors: Liming Yu, Mengen Zhai, Xiaowu Wang, Yang Yang, Liang Cheng, Haifeng Zhang, Qiang Meng, Yu Zhang, Shiqiang Yu, Weixun Duan
    Abstract:

    Abstract Melatonin confers cardioprotective effect against myocardial ischemia/reperfusion (MI/R) injury by reducing oxidative stress. Activation of silent information regulator 1 (SIRT1) signaling also reduces MI/R injury. We hypothesize that melatonin may protect against MI/R injury by activating SIRT1 signaling. This study investigated the protective effect of melatonin treatment on MI/R heart and elucidated its potential mechanisms. Rats were exposed to melatonin treatment in the presence or the absence of the melatonin receptor antagonist Luzindole or SIRT1 inhibitor EX527 and then subjected to MI/R operation. Melatonin conferred a cardioprotective effect by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase release, upregulating SIRT1, Bcl-2 expression and downregulating Bax, caspase-3 and cleaved caspase-3 expression. Melatonin treatment also resulted in reduced myocardium superoxide generation, gp91(phox) expression, malondialdehyde level, and increased myocardium superoxide dismutase (SOD) level, which indicate that the MI/R-induced oxidative stress was significantly attenuated. However, these protective effects were blocked by EX527 or Luzindole, indicating that SIRT1 signaling and melatonin receptor may be specifically involved in these effects. In summary, our results demonstrate that melatonin treatment attenuates MI/R injury by reducing oxidative stress damage via activation of SIRT1 signaling in a receptor-dependent manner.

N Tribulova - One of the best experts on this subject based on the ideXlab platform.

  • melatonin receptor activation protects against low potassium induced ventricular fibrillation by preserving action potentials and connexin 43 topology in isolated rat hearts
    Journal of Pineal Research, 2019
    Co-Authors: Natalia Jorgelina Prado, Tamara Egan Beňova, Emiliano Raul Diez, V Knezl, Boris Liptak, Amira Ponce Zumino, Mariano Llamedosoria, Barbara Szeiffova Bacova, Roberto M Miatello, N Tribulova
    Abstract:

    Hypokalemia prolongs the QRS and QT intervals, deteriorates intercellular coupling, and increases the risk for arrhythmia. Melatonin preserves gap junctions and shortens action potential as potential antiarrhythmic mechanisms, but its properties under hypokalemia remain unknown. We hypothesized that melatonin protects against low potassium-induced arrhythmias through the activation of its receptors, resulting in action potential shortening and connexin-43 preservation. After stabilization in Krebs-Henseleit solution (4.5 mEq/L K+ ), isolated hearts from Wistar rats underwent perfusion with low-potassium (1 mEq/L) solution and melatonin (100 μmol/L), a melatonin receptor blocker (Luzindole, 5 μmol/L), melatonin + Luzindole or vehicle. The primary endpoint of the study was the prevention of ventricular fibrillation. Electrocardiography was used, and epicardial action potentials and heart function were measured and analyzed. The ventricular expression, dephosphorylation, and distribution of connexin-43 were examined. Melatonin reduced the incidence of low potassium-induced ventricular fibrillation from 100% to 59%, delayed the occurrence of ventricular fibrillation and induced a faster recovery of sinus rhythm during potassium restitution. Melatonin prevented QRS widening, action potential activation delay, and the prolongation of action potential duration at 50% of repolarization. Other ECG and action potential parameters, the left ventricular developed pressure, and nonsustained ventricular arrhythmias did not differ among groups. Melatonin prevented connexin-43 dephosphorylation and its abnormal topology (lateralization). Luzindole abrogated the protective effects of melatonin on electrophysiological properties and connexin-43 misdistribution. Our results indicate that melatonin receptor activation protects against low potassium-induced ventricular fibrillation, shortens action potential duration, preserves ventricular electrical activation, and prevents acute changes in connexin-43 distribution. All of these properties make melatonin a remarkable antifibrillatory agent.

Huishan Wang - One of the best experts on this subject based on the ideXlab platform.

  • melatonin protects diabetic heart against ischemia reperfusion injury role of membrane receptor dependent cgmp pkg activation
    Biochimica et Biophysica Acta, 2018
    Co-Authors: Xue Dong, Yang Yang, Yong Zhang, Xiaodong Xue, Jian Zhang, Xiong Xiao, Jinsong Han, Yu Liu, Huishan Wang
    Abstract:

    It has been demonstrated that the anti-oxidative and cardioprotective effects of melatonin are, at least in part, mediated by its membrane receptors. However, the direct downstream signaling remains unknown. We previously found that melatonin ameliorated myocardial ischemia-reperfusion (MI/R) injury in diabetic animals, although the underlying mechanisms are also incompletely understood. This study was designed to determine the role of melatonin membrane receptors in melatonin's cardioprotective actions against diabetic MI/R injury with a focus on cGMP and its downstream effector PKG. Streptozotocin-induced diabetic Sprague-Dawley rats and high-glucose medium-incubated H9c2 cardiomyoblasts were utilized to determine the effects of melatonin against MI/R injury. Melatonin treatment preserved cardiac function and reduced oxidative damage and apoptosis. Additionally, melatonin increased intracellular cGMP level, PKGIα expression, p-VASP/VASP ratio and further modulated myocardial Nrf-2-HO-1 and MAPK signaling. However, these effects were blunted by KT5823 (a selective inhibitor of PKG) or PKGIα siRNA except that intracellular cGMP level did not changed significantly. Additionally, our in vitro study showed that Luzindole (a nonselective melatonin membrane receptor antagonist) or 4P-PDOT (a selective MT2 receptor antagonist) not only blocked the cytoprotective effect of melatonin, but also attenuated the stimulatory effect of melatonin on cGMP-PKGIα signaling and its modulatory effect on Nrf-2-HO-1 and MAPK signaling. This study showed that melatonin ameliorated diabetic MI/R injury by modulating Nrf-2-HO-1 and MAPK signaling, thus reducing myocardial apoptosis and oxidative stress and preserving cardiac function. Importantly, melatonin membrane receptors (especially MT2 receptor)-dependent cGMP-PKGIα signaling played a critical role in this process.

  • melatonin rescues cardiac thioredoxin system during ischemia reperfusion injury in acute hyperglycemic state by restoring notch1 hes1 akt signaling in a membrane receptor dependent manner
    Journal of Pineal Research, 2017
    Co-Authors: Liming Yu, Yinli Xu, Zhi Li, Guolong Zhao, Yang Yang, Huishan Wang
    Abstract:

    Stress hyperglycemia is commonly observed in patients suffering from ischemic heart disease. It not only worsens cardiovascular prognosis but also attenuates the efficacies of various cardioprotective agents. This study aimed to investigate the protective effect of melatonin against myocardial ischemia-reperfusion (MI/R) injury in acute hyperglycemic state with a focus on Notch1/Hes1/Akt signaling and intracellular thioredoxin (Trx) system. Sprague-Dawley rats were subjected to MI/R surgery and high glucose (HG, 500 g/L) infusion (4 ml/kg/h) to induce temporary hyperglycemia. Rats were treated with or without melatonin (10 mg/kg/d) during the operation. Furthermore, HG (33mM) incubated H9c2 cardiomyoblasts were treated in the presence or absence of Luzindole (a competitive melatonin receptor antagonist), DAPT (a γ-Secretase inhibitor), LY294002 (a PI3-kinase/Akt inhibitor) or thioredoxin-interacting protein (Txnip) adenoviral vectors. We found that acute hyperglycemia aggravated MI/R injury by suppressing Notch1/Hes1/Akt signaling and intracellular Trx activity. Melatonin treatment effectively ameliorated MI/R injury by reducing infarct size, myocardial apoptosis and oxidative stress. Moreover, melatonin also markedly enhanced Notch1/Hes1/Akt signaling and rescued intracellular Trx system by up-regulating Notch1, N1ICD, Hes1 and p-Akt expressions, increasing Trx activity and down-regulated Txnip expression. However, these effects were blunted by Luzindole, DAPT or LY294002. Additionally, Txnip overexpression not only decreased Trx activity, but also attenuated the cytoprotective effect of melatonin. We conclude that impaired Notch1 signaling aggravates MI/R injury in acute hyperglycemic state. Melatonin rescues Trx system by reducing Txnip expression via Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner. Its role as a prophylactic/therapeutic drug deserves further clinical study. This article is protected by copyright. All rights reserved.

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