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Piceatannol attenuates homocysteine-induced endoplasmic reticulum stress and endothelial cell damage via heme oxygenase-1 expression

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Abstract

A growing body of evidence implicates endoplasmic reticulum (ER)-induced cellular dysfunction and apoptosis as important factors to a variety of diseases. In endothelial cells (ECs), the sulfur-containing amino acid homocysteine (Hcy) causes EC apoptosis and reactive oxygen species (ROS) generation through induction of ER stress. Here, we have investigated whether piceatannol (Pic), a resveratrol analog, could protect ECs against Hcy-induced apoptosis, oxidative stress and ER stress, with specific emphasis on heme oxygenase-1 (HO-1). In human ECs, we determined the effects of Hcy and Pic on annexin V positivity, glucose-regulated protein 78 kDa (GRP78) and C/EBP homologous protein (CHOP) expression, X-box binding protein 1 (Xbp-1) mRNA slicing, and ROS-sensitive dihydroethidium (DHE) oxidation. Hcy increased annexin V-positive cells, DHE oxidation, GRP78 and CHOP expression and Xbp-1 mRNA splicing, indicating that Hcy induces apoptosis, oxidative stress and ER stress. Pretreatment of ECs with Pic significantly inhibited Hcy-induced apoptosis, ROS generation and ER stress. Pic also increased HO-1 expression via activation of nuclear factor-E2-related factor 2 (Nrf2). Interestingly, the inhibitory effects of Pic on Hcy-induced apoptosis, ROS generation and ER stress were abolished by down-regulation of HO-1 expression, while mimicked by treatment of ECs with the HO-1 inducer hemin. Overall, these results suggest that Pic may protect ECs against Hcy-induced apoptosis, oxidative stress and ER stress via Nrf2-dependent HO-1 expression.

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Abbreviations

7-AAD:

7-Aminoactinomycin D

ARE:

Antioxidant responsive element

CHOP:

C/EBP homologous protein

DHE:

Dihydroethidium

EC:

Endothelial cell

ELISA:

Enzyme-linked immunosolvent assay

ER:

Endoplasmic reticulum

GRP78:

Glucose-regulated protein 78 kDa

Hcy:

Homocysteine

HO-1:

Heme oxygenase-1

IRE1:

Inositol-requiring ER-to-nucleus signal kinase 1

Luci:

Luciferase

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrozolium bromide

NC:

Non-targeting control

Nrf2:

Nuclear factor-E2-related factor 2

Nrf2-DN:

Nrf2 dominant negative mutant

PE:

Phycoerythrin

PERK:

RNA-dependent protein kinase-like ER kinase

Pic:

Piceatannol

ROS:

Reactive oxygen species

RT-PCR:

Reverse transcription reaction

RuCO:

Tricarbonyldichlororuthenium (II) dimer

SDS:

Dodecyl sulfate

siRNA:

Small interfering RNA

UPR:

Unfolded protein response

Xbp-1:

X-box binding protein 1

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Acknowledgements

This work was supported by the National Research Foundation of Korea funded by the Korean government (MSIP) (No. 2011-0030130) and by the Bio and Medical Technology Development Program of the National Research Foundation funded by the Ministry of Science, ICT and Future Planning (No. 2012M3A9C3048686).

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    Authors and Affiliations

    1. Department of Neurosurgery, Wonkwang University School of Medicine, Iksan, 54538, Republic of Korea

      Jin-Sang Kil

    2. Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan, 54538, Republic of Korea

      Sun-Oh Jeong & Hyun-Ock Pae

    3. Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea

      Hun-Taeg Chung

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    Correspondence to Hyun-Ock Pae.

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    The authors declare that they have no conflict of interest.

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    Informed consent was waived, because we used an established human cell line that commercially is available.

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    J.-S. Kil and S.-Oh Jeong contributed equally to this work.

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    Kil, JS., Jeong, SO., Chung, HT. et al. Piceatannol attenuates homocysteine-induced endoplasmic reticulum stress and endothelial cell damage via heme oxygenase-1 expression. Amino Acids 49, 735–745 (2017). https://doi.org/10.1007/s00726-016-2375-0

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