Endoplasmic reticulum stress participates in aortic valve calcification in hypercholesterolemic animals.
OBJECTIVE
Aortic valve (AV) calcification occurs via a pathophysiological process that includes lipoprotein deposition, inflammation, and osteoblastic differentiation of valvular interstitial cells. Here, we investigated the association between endoplasmic reticulum (ER) stress and AV calcification.


RESULTS
We identified ER stress activation in AV of patients with calcified AV stenosis. We generated an AV calcification model in hypercholesterolemic rabbits and mice, respectively, and found marked AV ER stress induction. Classical ER stress inhibitor, tauroursodeoxycholic acid, administration markedly prevented AV calcification, and attenuated AV osteoblastic differentiation and inflammation in both rabbit and mouse models of AV calcification via inhibition of ER stress. In cultured valvular interstitial cells (VICs), we found that oxidized low density lipoprotein (oxLDL) caused ER stress in a cytosolic [Ca](2+)i-dependent manner. OxLDL promoted osteoblastic differentiation via ER stress-mediated protein kinase-like ER kinase/activating transcription factor 4/osteocalcin and inositol-requiring transmembrane kinase and endonuclease-1α (IRE1α)/spliced X-box-binding protein 1/Runx2 pathway, and induced inflammatory responses through IRE1α/c-Jun N-terminal kinase and IRE1α/nuclear factor kappa-light-chain-enhancer of activated B cells signaling in VICs. Inhibition of ER stress by either tauroursodeoxycholic acid or 4-phenyl butyric acid could both suppress oxLDL-induced osteoblastic differentiation and inflammatory responses in VICs.


CONCLUSIONS
These data provide novel evidence that ER stress participates in AV calcification development, and suggest that ER stress may be a novel target for AV calcification prevention and treatment.
From the Institute of Hypertension and Department of Internal Medicine, Tongji Hospital (Z.C., W.G., Q.D., C.C., L.N., D.W.W.), and Department of Cardiovascular Surgery, Union Hospital (F.L., N.D.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Second Affiliated Hospital, Medical College, Zhejiang University, Hangzhou, China (Z.C.); Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Molecular and Cellular Biochemistry, Ohio State University College of Medicine, Columbus, OH (Y.X.); and Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, Canada (K.C.).
Zhejun
Z
Cai
Fei
F
Li
Wei
W
Gong
Wanjun
W
Liu
Quanlu
Q
Duan
Chen
C
Chen
Li
L
Ni
Yong
Y
Xia
Katherine
K
Cianflone
Nianguo
N
Dong
Dao Wen
DW
Wang
D000368:Aged; D000818:Animals; D001021:Aortic Valve / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002114:Calcinosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010654:Phenylbutyrates / Q000494:pharmacology; D034622:RNA Interference; D011817:Rabbits; D015398:Signal Transduction; D013552:Swine; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D014162:Transfection
D001057:Apolipoproteins E; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D010654:Phenylbutyrates; C099252:oxidized low density lipoprotein; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; C075773:4-phenylbutyric acid; D002118:Calcium
aortic valve, calcification of; endoplasmic reticulum stress; inflammation; osteogenesis; oxidized low density lipoprotein; tauroursodeoxycholic acid