Metformin protects endothelial function in diet-induced obese mice by inhibition of endoplasmic reticulum stress through 5' adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor δ pathway.
OBJECTIVE
5' Adenosine monophosphate-activated protein kinase (AMPK) interacts with peroxisome proliferator-activated receptor δ (PPARδ) to induce gene expression synergistically, whereas the activation of AMPK inhibits endoplasmic reticulum (ER) stress. Whether the vascular benefits of antidiabetic drug metformin (AMPK activator) in diabetes mellitus and obesity is mediated by PPARδ remains unknown. We aim to investigate whether PPARδ is crucial for metformin in ameliorating ER stress and endothelial dysfunction induced by high-fat diet.


RESULTS
Acetylcholine-induced endothelium-dependent relaxation in aortae was measured on wire myograph. ER stress markers were determined by Western blotting. Superoxide production in mouse aortae and NO generation in mouse aortic endothelial cells were assessed by fluorescence imaging. Endothelium-dependent relaxation was impaired and ER stress markers and superoxide level were elevated in aortae from high-fat diet-induced obese mice compared with lean mice. These effects of high-fat diet were reversed by oral treatment with metformin in diet-induced obese PPARδ wild-type mice but not in diet-induced obese PPARδ knockout littermates. Metformin and PPARδ agonist GW1516 reversed tunicamycin (ER stress inducer)-induced ER stress, oxidative stress, and impairment of endothelium-dependent relaxation in mouse aortae as well as NO production in mouse aortic endothelial cells. Effects of metformin were abolished by cotreatment of GSK0660 (PPARδ antagonist), whereas effects of GW1516 were unaffected by compound C (AMPK inhibitor).


CONCLUSIONS
Metformin restores endothelial function through inhibiting ER stress and oxidative stress and increasing NO bioavailability on activation of AMPK/PPARδ pathway in obese diabetic mice.
From Institute of Vascular Medicine, Shenzhen Research Institute, and Li Ka Shing Institute of Health Sciences (W.S.C., X.Y.T., C.W.L., X.Y., Y.H.), and School of Life Sciences (S.S.-T.L., Z.Y.C.), Chinese University of Hong Kong, Hong Kong, China; Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX (X.Y.T., W.T.W.); and Cardiovascular Research Center, Xi'an Jiaotong University, Xi'an, China (N.W.).
Wai San
WS
Cheang
Xiao Yu
XY
Tian
Wing Tak
WT
Wong
Chi Wai
CW
Lau
Susanna Sau-Tuen
SS
Lee
Zhen Yu
ZY
Chen
Xiaoqiang
X
Yao
Nanping
N
Wang
Yu
Y
Huang
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D004789:Enzyme Activation; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists* / Q000172:deficiency / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000975:Antioxidants; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D014665:Vasodilator Agents; D013481:Superoxides; D009569:Nitric Oxide; D008687:Metformin; D055372:AMP-Activated Protein Kinases
endothelium; nitric oxide; obesity; vasodilation