Salsalate ameliorates the atherosclerotic response through HO-1- and SIRT1-mediated suppression of ER stress and inflammation

Tae Woo Jung, Hyung Sub Park, Ji Hoon Jeong, Taeseung Lee

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Objective and design: Inflammation plays a causative role in atherosclerosis development. Salsalate is an anti-inflammatory drug used to treat atherosclerosis, but the mechanisms by which it affects atherosclerotic progression remain unclear. Methods: Human umbilical vascular endothelial cells (HUVECs) and THP-1 human monocytes were treated with salsalate. Heme oxygenase 1 (HO-1) and sirtuin 1 (SIRT1) small interfering RNAs (siRNAs) were used to suppress each gene expression. Protein analyses were performed for measuring the expression of HO-1, SIRT1, nuclear factor kappa B (NFκB), cell adhesion molecules, and endoplasmic reticulum (ER) stress markers. Furthermore, cell adhesion assay, caspase 3 activity assay, and ELISA were also performed. Results: In this study, we show that salsalate increases the expression of HO-1 and SIRT1 in HUVEC and suppresses lipopolysaccharide (LPS)-induced atherosclerotic responses via HO-1- and SIRT1-mediated pathways. Salsalate treatment of HUVEC and THP-1 cells reduced LPS-induced phosphorylation of NFκB and secretion of the proinflammatory cytokines TNFα and MCP-1. Salsalate treatment of HUVEC reduced the expression of the adhesion molecules ICAM, VCAM, and E-selectin and the LPS-induced adhesion of THP-1 cells to HUVEC. Salsalate treatment also attenuated LPS-induced ER stress and cell apoptosis. These anti-atherosclerotic effects were reversed by treating cells with siRNA for HO-1 and SIRT1. Conclusions: Salsalate ameliorates LPS-induced atherosclerotic reactions via HO-1 and SIRT1-dependent reduction of inflammation and ER stress. Activation of these pathways by salsalate may provide therapeutic strategies for treating atherosclerosis.

Original languageEnglish
Pages (from-to)655-663
Number of pages9
JournalInflammation Research
Volume68
Issue number8
DOIs
StatePublished - 2 Aug 2019

Fingerprint

Sirtuin 1
Heme Oxygenase-1
Endoplasmic Reticulum Stress
Umbilicus
Inflammation
Lipopolysaccharides
Endothelial Cells
Atherosclerosis
NF-kappa B
Small Interfering RNA
E-Selectin
salicylsalicylic acid
Cell Adhesion Molecules
Therapeutics
Cell Adhesion
Caspase 3
Monocytes
B-Lymphocytes
Anti-Inflammatory Agents
Enzyme-Linked Immunosorbent Assay

Keywords

  • Apoptosis
  • ER stress
  • HUVEC
  • Heme oxygenase 1
  • Inflammation
  • SIRT1
  • Salsalate
  • THP-1

Cite this

@article{79c5d2b7a8c6477c8fb6013c71e8b5ed,
title = "Salsalate ameliorates the atherosclerotic response through HO-1- and SIRT1-mediated suppression of ER stress and inflammation",
abstract = "Objective and design: Inflammation plays a causative role in atherosclerosis development. Salsalate is an anti-inflammatory drug used to treat atherosclerosis, but the mechanisms by which it affects atherosclerotic progression remain unclear. Methods: Human umbilical vascular endothelial cells (HUVECs) and THP-1 human monocytes were treated with salsalate. Heme oxygenase 1 (HO-1) and sirtuin 1 (SIRT1) small interfering RNAs (siRNAs) were used to suppress each gene expression. Protein analyses were performed for measuring the expression of HO-1, SIRT1, nuclear factor kappa B (NFκB), cell adhesion molecules, and endoplasmic reticulum (ER) stress markers. Furthermore, cell adhesion assay, caspase 3 activity assay, and ELISA were also performed. Results: In this study, we show that salsalate increases the expression of HO-1 and SIRT1 in HUVEC and suppresses lipopolysaccharide (LPS)-induced atherosclerotic responses via HO-1- and SIRT1-mediated pathways. Salsalate treatment of HUVEC and THP-1 cells reduced LPS-induced phosphorylation of NFκB and secretion of the proinflammatory cytokines TNFα and MCP-1. Salsalate treatment of HUVEC reduced the expression of the adhesion molecules ICAM, VCAM, and E-selectin and the LPS-induced adhesion of THP-1 cells to HUVEC. Salsalate treatment also attenuated LPS-induced ER stress and cell apoptosis. These anti-atherosclerotic effects were reversed by treating cells with siRNA for HO-1 and SIRT1. Conclusions: Salsalate ameliorates LPS-induced atherosclerotic reactions via HO-1 and SIRT1-dependent reduction of inflammation and ER stress. Activation of these pathways by salsalate may provide therapeutic strategies for treating atherosclerosis.",
keywords = "Apoptosis, ER stress, HUVEC, Heme oxygenase 1, Inflammation, SIRT1, Salsalate, THP-1",
author = "Jung, {Tae Woo} and Park, {Hyung Sub} and Jeong, {Ji Hoon} and Taeseung Lee",
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language = "English",
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journal = "Inflammation Research",
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}

Salsalate ameliorates the atherosclerotic response through HO-1- and SIRT1-mediated suppression of ER stress and inflammation. / Jung, Tae Woo; Park, Hyung Sub; Jeong, Ji Hoon; Lee, Taeseung.

In: Inflammation Research, Vol. 68, No. 8, 02.08.2019, p. 655-663.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Salsalate ameliorates the atherosclerotic response through HO-1- and SIRT1-mediated suppression of ER stress and inflammation

AU - Jung, Tae Woo

AU - Park, Hyung Sub

AU - Jeong, Ji Hoon

AU - Lee, Taeseung

PY - 2019/8/2

Y1 - 2019/8/2

N2 - Objective and design: Inflammation plays a causative role in atherosclerosis development. Salsalate is an anti-inflammatory drug used to treat atherosclerosis, but the mechanisms by which it affects atherosclerotic progression remain unclear. Methods: Human umbilical vascular endothelial cells (HUVECs) and THP-1 human monocytes were treated with salsalate. Heme oxygenase 1 (HO-1) and sirtuin 1 (SIRT1) small interfering RNAs (siRNAs) were used to suppress each gene expression. Protein analyses were performed for measuring the expression of HO-1, SIRT1, nuclear factor kappa B (NFκB), cell adhesion molecules, and endoplasmic reticulum (ER) stress markers. Furthermore, cell adhesion assay, caspase 3 activity assay, and ELISA were also performed. Results: In this study, we show that salsalate increases the expression of HO-1 and SIRT1 in HUVEC and suppresses lipopolysaccharide (LPS)-induced atherosclerotic responses via HO-1- and SIRT1-mediated pathways. Salsalate treatment of HUVEC and THP-1 cells reduced LPS-induced phosphorylation of NFκB and secretion of the proinflammatory cytokines TNFα and MCP-1. Salsalate treatment of HUVEC reduced the expression of the adhesion molecules ICAM, VCAM, and E-selectin and the LPS-induced adhesion of THP-1 cells to HUVEC. Salsalate treatment also attenuated LPS-induced ER stress and cell apoptosis. These anti-atherosclerotic effects were reversed by treating cells with siRNA for HO-1 and SIRT1. Conclusions: Salsalate ameliorates LPS-induced atherosclerotic reactions via HO-1 and SIRT1-dependent reduction of inflammation and ER stress. Activation of these pathways by salsalate may provide therapeutic strategies for treating atherosclerosis.

AB - Objective and design: Inflammation plays a causative role in atherosclerosis development. Salsalate is an anti-inflammatory drug used to treat atherosclerosis, but the mechanisms by which it affects atherosclerotic progression remain unclear. Methods: Human umbilical vascular endothelial cells (HUVECs) and THP-1 human monocytes were treated with salsalate. Heme oxygenase 1 (HO-1) and sirtuin 1 (SIRT1) small interfering RNAs (siRNAs) were used to suppress each gene expression. Protein analyses were performed for measuring the expression of HO-1, SIRT1, nuclear factor kappa B (NFκB), cell adhesion molecules, and endoplasmic reticulum (ER) stress markers. Furthermore, cell adhesion assay, caspase 3 activity assay, and ELISA were also performed. Results: In this study, we show that salsalate increases the expression of HO-1 and SIRT1 in HUVEC and suppresses lipopolysaccharide (LPS)-induced atherosclerotic responses via HO-1- and SIRT1-mediated pathways. Salsalate treatment of HUVEC and THP-1 cells reduced LPS-induced phosphorylation of NFκB and secretion of the proinflammatory cytokines TNFα and MCP-1. Salsalate treatment of HUVEC reduced the expression of the adhesion molecules ICAM, VCAM, and E-selectin and the LPS-induced adhesion of THP-1 cells to HUVEC. Salsalate treatment also attenuated LPS-induced ER stress and cell apoptosis. These anti-atherosclerotic effects were reversed by treating cells with siRNA for HO-1 and SIRT1. Conclusions: Salsalate ameliorates LPS-induced atherosclerotic reactions via HO-1 and SIRT1-dependent reduction of inflammation and ER stress. Activation of these pathways by salsalate may provide therapeutic strategies for treating atherosclerosis.

KW - Apoptosis

KW - ER stress

KW - HUVEC

KW - Heme oxygenase 1

KW - Inflammation

KW - SIRT1

KW - Salsalate

KW - THP-1

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SN - 1023-3830

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