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Protective effect of low dose gadolinium chloride against isoproterenol-induced myocardial injury in rat

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Abstract

Acute myocardial injury remains a leading cause of morbidity and mortality worldwide, and large amount of released arachidonic acid (AA) is found to be related to cardiomyocyte apoptosis and necrosis. Previous study suggested that GdCl3 completely abolished AA-induced Ca2+ response. Thus, this study aims to investigate possible cardioprotection effect of GdCl3 on isoproterenol (ISO)-induced myocardial injury and its underlying mechanism(s). Rats that were randomly allocated to five groups: control, GdCl3, ISO, ISO + GdCl3, and ISO + verapamil. Serum levels of AA and cardiac markers, infarct area, and cell apoptosis in heart were measured by ELISA assay, TTC and TUNEL staining, respectively. Chemical interaction between AA and GdCl3 was evaluated by mass and UV spectrometry. The expressions and translocations of death receptor related molecules into lipid rafts were detected in neonatal rat ventricular myocytes by Western blots. Compared with ISO-administered rats, GdCl3 significantly ameliorated the myocardium injury, demonstrated by restoring serum cardiac troponin I, lactate dehydrogenase, creatine kinase MB and AA to near normal levels, and decreasing infarct area and cell apoptosis. In addition, an activation of AA-Fas pathway was found in ISO-induced myocardial injury, which was abrogated by GdCl3. Furthermore, AA induced cell apoptosis through clustering and activating death receptor related molecules TNFR1, Fas and FADD in lipid rafts, a process significantly prevented by the pretreatment with GdCl3. Finally, GdCl3 at the molar ratio of 1/3 (GdCl3/AA) was mostly effective in abolishing AA-induced Ca2+ response and cell apoptosis, because an obvious change in the chemical identity of AA was obtained by GdCl3 according to this molar ratio. In conclusion, this study demonstrates for the first time that GdCl3 protects myocardium against ISO-induced cell apoptosis through, at least partly, serving as a scavenger of AA, therefore abolishing its downstream activation of the death receptor regulated apoptosis pathway.

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Abbreviations

AA:

Arachidonic acid

cTnI:

Cardiac troponin I

CK-MB:

Creatine kinase MB

FADD:

Fas-associated death domain-containing protein

ISO:

Isoproterenol

LDH:

Lactate dehydrogenase

Mβ-CD:

Methyl-β-cyclodextrin

MBS:

Morpholine ethanesulfonic acid-buffered saline

NRVMs:

Neonatal rat ventricular myocytes

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Acknowledgments

This study was supported by grants from National Natural Science Foundation (81302777, 81370339) and Beijing Key Laboratory of Cardiovascular Diseases Related to Metabolic Disturbance (Z13111000280000).

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Authors and Affiliations

  1. Department of Pharmacology, Capital Medical University, Street of Youanmenwai, #10 Xitoutiao, District of Feng Tai, Beijing, 100069, People’s Republic of China

    Yuan-Yuan Zheng, Hai-Hong Zhang, Xin-Xin Yan, Min Chen, Tian-Yu Qi, Lan-E Zhang & Da-Li Luo

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Correspondence to Da-Li Luo.

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Conflict of interest

The authors declare that they have no competing interests.

Compliance with ethical standards

The animal study was carried out in strict accordance with the recommendations in the ‘Guide for the Care and Use of Laboratory Animals’ published by the US National Institutes of Health (publication No. 85-23, revised 1996). All animal care and protocols were approved by the Animal Care Committee of Capital Medical University, Beijing, China. All animals were euthanized under chloral hydrate anesthesia, and every effort was made to minimize animal suffering.

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Informed consent was obtained from all individual participants included in the study.

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S. Fig. 1

Concentration-dependent inhibitions on AA-mediated intracellular Ca2+ signaling by GdCl3. a Intracellular Ca2+ signals were measured in HEK293 cells which were incubated in the presence of AA (10-100 μM) and different concentrations of GdCl3 as indicated with the arrows. b Summary data for intracellular Ca2+ signals with the indicated treatments. Experiments were repeated a minimum of three times.. Supplementary material 1 (TIFF 244 kb)

S. Fig. 2

Inhibition on KCl- or AA-mediated intracellular Ca2+ signals by GdCl3 or verapamil. a NRVMs incubated in HBSS buffer were pretreated with GdCl3 (5 μM, 3 min) or verapamil (1 μM, 3 min) and followed by the exposure to AA (10 μM), and intracellular Ca2+ signals at different time points were measured as indicated with the arrows. b NRVMs incubated in HBSS buffer were pretreated with GdCl3 (5 μM, 3 min) or verapamil (1 μM, 3 min) and followed by the exposure to high KCl (50 mM), and intracellular Ca2+ signals were measured as indicated with the arrows. Experiments were repeated a minimum of three times. Supplementary material 2 (TIFF 560 kb)

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Zheng, YY., Zhang, HH., Yan, XX. et al. Protective effect of low dose gadolinium chloride against isoproterenol-induced myocardial injury in rat. Apoptosis 20, 1164–1175 (2015). https://doi.org/10.1007/s10495-015-1147-8

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