title: Paeonol protects against endoplasmic reticulum stress-induced endothelial dysfunction via AMPK/PPARδ signaling pathway.
abstract: Endoplasmic reticulum (ER) stress in endothelial cells often leads to endothelial dysfunction which underlies the pathogenesis of cardiovascular diseases. Paeonol, a major phenolic component extracted from Moutan Cortex, possesses various medicinal benefits which have been used extensively in traditional Chinese medicine. The present study investigated the protective mechanism of paeonol against tunicamycin-induced ER stress in isolated mouse aortas and human umbilical vein endothelial cells (HUVECs). Vascular reactivity in aorta was measured using a wire myograph. The effects of paeonol on protein expression of ER stress markers, reactive oxygen species (ROS) production, nitric oxide (NO) bioavailability and peroxisome proliferator-activated receptor δ (PPARδ) activity in the vascular wall were assessed by Western blot, dihydroethidium fluorescence (DHE) or lucigenin enhanced-chemiluminescence, 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM DA) and dual luciferase reporter assay, respectively. Ex vivo treatment with paeonol (0.1μM) for 16h reversed the impaired endothelium-dependent relaxations in C57BJ/6J and PPARδ wild type (WT) mouse aortas following incubation with tunicamycin (0.5μg/mL). Elevated ER stress markers, oxidative stress and reduction of NO bioavailability induced by tunicamycin in HUVECs, C57BJ/6J and PPARδ WT mouse aortas were reversed by paeonol treatment. These beneficial effects of paeonol were diminished in PPARδ knockout (KO) mouse aortas. Paeonol increased the expression of 5' adenosine monophosphate-activated protein kinase (AMPK) and PPARδ expression and activity while restoring the decreased phosphorylation of eNOS. The present study delineates that paeonol protects against tunicamycin-induced vascular endothelial dysfunction by inhibition of ER stress and oxidative stress, thus elevating NO bioavailability via the AMPK/PPARδ signaling pathway.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Ker-Woon
authors.initials: KW
authors.lastname: Choy
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. Electronic address: rais@um.edu.my.
authors.forename: Mohd Rais
authors.initials: MR
authors.lastname: Mustafa
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Yeh Siang
authors.initials: YS
authors.lastname: Lau
authors.affiliation: Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Dharmani
authors.initials: D
authors.lastname: Murugan
authors.affiliation: Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Lau
authors.affiliation: Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China. Electronic address: yu-huang@cuhk.edu.hk.
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001013:Aorta, Thoracic; D002460:Cell Line; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000819:agonists / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000737:chemistry / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047494:PPAR delta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D046509:Tissue Culture Techniques
chemical_list: D000098:Acetophenones; D000975:Antioxidants; D047494:PPAR delta; D011994:Recombinant Proteins; D009569:Nitric Oxide; C013638:paeonol; D052250:Nitric Oxide Synthase Type III; D055372:AMP-Activated Protein Kinases
keywords: 5′ adenosine monophosphate-activated protein kinase; A23187 (PubChem CID: 11957499); DAF-FM-DA (PubChem CID: 2762646); Endoplasmic reticulum stress; Endothelial dysfunction; GSK0660 (PubChem CID: 46233311); GW1516 (PubChem CID: 9803963); Paeonol; Peroxisome proliferator-activated receptor δ; TUDCA (PubChem CID: 9848818); Tunicamycin; acetylcholine (PubChem CID: 187); compound C (PubChem CID: 11524144); dihydroethidium (PubChem CID: 128682); paeonol (PubChem CID: 11092); phenylephrine (PubChem CID: 6041); tunicamycin (PubChem CID: 11104835)