Ceramide enhances COX-2 expression and VSMC contractile hyperreactivity via ER stress signal activation

Huina Zhang; Juanfen Li; Linghai Li; Pingsheng Liu; Yongxiang Wei; Zongjie Qian

doi:10.1016/j.vph.2017.08.001

Ceramide enhances COX-2 expression and VSMC contractile hyperreactivity via ER stress signal activation

Vascul Pharmacol. 2017 Sep:96-98:26-32. doi: 10.1016/j.vph.2017.08.001. Epub 2017 Aug 7.

Authors

Huina Zhang¹, Juanfen Li², Linghai Li³, Pingsheng Liu⁴, Yongxiang Wei⁵, Zongjie Qian⁶

Affiliations

¹ Beijing An Zhen Hospital, Capital Medical University, Key Laboratory of Upper Airway Dysfunction-related Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China. Electronic address: [email protected].
² Department of Cardiovascular Medicine, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China.
³ Department of Anesthesiology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
⁴ National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
⁵ Beijing An Zhen Hospital, Capital Medical University, Key Laboratory of Upper Airway Dysfunction-related Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, China.
⁶ Department of Cardiovascular Medicine, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China. Electronic address: [email protected].

PMID: 28797762
DOI: 10.1016/j.vph.2017.08.001

Abstract

Ceramide accumulation in blood vessels has been attributed to vascular dysfunction in progressive vascular complications in metabolic diseases. The present study showed that ceramide pretreatment promoted PE-induced vasoconstriction in rat endothelium-denuded vascular rings in a time- and dose-dependent manner. Endoplasmic reticulum (ER) stress inhibitors, 4-PBA and TUDCA, COX-2 inhibitors, Celecoxib and NS398, as well as PGE₂ receptor antagonist AH-6809 attenuated ceramide-promoted vascular hyperreactivity. Ceramide promoted the transcriptional and translational expression of COX-2 and BiP in VSMCs, which were blocked by the ER stress inhibitors, 4-PBA and TUDCA. These findings show that ceramide enhances PE-induced vascular smooth muscle constriction by mediation of the ER stress/COX-2/PGE₂ pathway. Therapeutic strategies targeted to reducing ER stress and COX-2 activation might be beneficial in attenuating vascular complications.

Chemical compounds: C₂-Ceramide (N-acetyl-d-erythro-sphingosine) CID:2662 Tauroursodeoxycholic Acid Sodium (TUDCA) CID:9848818 phenylephrine (PE) CID:6041.

Keywords: COX-2; Ceramide; ER stress; Vasoconstriction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aorta, Thoracic / drug effects
Aorta, Thoracic / enzymology
Cell Line
Cyclooxygenase 2 / genetics
Cyclooxygenase 2 / metabolism*
Dinoprostone / metabolism
Dose-Response Relationship, Drug
Endoplasmic Reticulum Stress / drug effects*
In Vitro Techniques
Mesenteric Arteries / drug effects
Mesenteric Arteries / enzymology
Muscle, Smooth, Vascular / drug effects*
Muscle, Smooth, Vascular / enzymology
Myocytes, Smooth Muscle / drug effects*
Myocytes, Smooth Muscle / enzymology
Rats, Sprague-Dawley
Signal Transduction / drug effects
Sphingosine / analogs & derivatives*
Sphingosine / pharmacology
Time Factors
Transfection
Up-Regulation
Vasoconstriction / drug effects*

Substances

N-acetylsphingosine
Cyclooxygenase 2
Ptgs2 protein, rat
Dinoprostone
Sphingosine