| Aberrant endoplasmic reticulum stress in vascular smooth muscle increases vascular contractility and blood pressure in mice deficient of AMP-activated protein kinase-α2 in vivo. | |
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MedLine Citation:
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PMID: 23288166 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: The endoplasmic reticulum (ER) plays a critical role in ensuring proper folding of newly synthesized proteins. Aberrant ER stress is reported to play a causal role in cardiovascular diseases. However, the effects of ER stress on vascular smooth muscle contractility and blood pressure remain unknown. The aim of this study was to investigate whether aberrant ER stress causes abnormal vasoconstriction and consequent high blood pressure in mice. METHODS AND RESULTS: ER stress markers, vascular smooth muscle contractility, and blood pressure were monitored in mice. Incubation of isolated aortic rings with tunicamycin or MG132, 2 structurally unrelated ER stress inducers, significantly increased both phenylephrine-induced vasoconstriction and the phosphorylation of myosin light chain (Thr18/Ser19), both of which were abrogated by pretreatment with chemical chaperones or 5-Aminoimidazole-4-carboxamide ribonucleotide and metformin, 2 potent activators for the AMP-activated protein kinase. Consistently, administration of tauroursodeoxycholic acid or 4-phenyl butyric acid, 2 structurally unrelated chemical chaperones, in AMP-activated protein kinase-α2 knockout mice lowered blood pressure and abolished abnormal vasoconstrictor response of AMP-activated protein kinase-α2 knockout mice to phenylephrine. Consistently, tunicamycin (0.01 μg/g per day) infusion markedly increased both systolic and diastolic blood pressure, both of which were ablated by coadministration of 4-phenyl butyric acid. Furthermore, 4-phenyl butyric acid or tauroursodeoxycholic acid, which suppressed angiotensin II infusion-induced ER stress markers in vivo, markedly lowered blood pressure in angiotensin II-infused mice in vivo. CONCLUSIONS: We conclude that ER stress increases vascular smooth muscle contractility resulting in high blood pressure, and AMP-activated protein kinase activation mitigates high blood pressure through the suppression of ER stress in vivo. |
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Authors:
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Bin Liang; Shuangxi Wang; Qilong Wang; Wencheng Zhang; Benoit Viollet; Yi Zhu; Ming-Hui Zou |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2013-01-03 |
Journal Detail:
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Title: Arteriosclerosis, thrombosis, and vascular biology Volume: 33 ISSN: 1524-4636 ISO Abbreviation: Arterioscler. Thromb. Vasc. Biol. Publication Date: 2013 Mar |
Date Detail:
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Created Date: 2013-02-14 Completed Date: 2013-04-10 Revised Date: 2013-06-13 |
Medline Journal Info:
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Nlm Unique ID: 9505803 Medline TA: Arterioscler Thromb Vasc Biol Country: United States |
Other Details:
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Languages: eng Pagination: 595-604 Citation Subset: IM |
Affiliation:
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Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA. |
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| MeSH Terms | |
Descriptor/Qualifier:
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AMP-Activated Protein Kinases
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deficiency*,
genetics Aminoimidazole Carboxamide / analogs & derivatives, pharmacology Angiotensin II Animals Antihypertensive Agents / pharmacology Blood Pressure* / drug effects Cells, Cultured Disease Models, Animal Dose-Response Relationship, Drug Endoplasmic Reticulum Stress* / drug effects Enzyme Activation Enzyme Activators / pharmacology Humans Hypertension / chemically induced, enzymology*, physiopathology, prevention & control Leupeptins / pharmacology Mice Mice, Knockout Muscle, Smooth, Vascular / drug effects, enzymology* Myosin Light Chains / metabolism Nitric Oxide Synthase Type III / deficiency, genetics Phenylbutyrates / pharmacology Phenylephrine / pharmacology Phosphorylation Ribonucleotides / pharmacology Taurochenodeoxycholic Acid / pharmacology Time Factors Tunicamycin / pharmacology Vasoconstriction* / drug effects Vasoconstrictor Agents / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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R01 HL074399/HL/NHLBI NIH HHS; R01 HL079584/HL/NHLBI NIH HHS; R01 HL080499/HL/NHLBI NIH HHS; R01 HL089920/HL/NHLBI NIH HHS; R01 HL096032/HL/NHLBI NIH HHS; R01 HL105157/HL/NHLBI NIH HHS; R01 HL110488/HL/NHLBI NIH HHS; R01HL074399/HL/NHLBI NIH HHS; R01HL079584/HL/NHLBI NIH HHS; R01HL080499/HL/NHLBI NIH HHS; R01HL08920/HL/NHLBI NIH HHS; R01HL096032/HL/NHLBI NIH HHS; R01HL105157/HL/NHLBI NIH HHS; R01HL110488/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antihypertensive Agents; 0/Enzyme Activators; 0/Leupeptins; 0/Myosin Light Chains; 0/Phenylbutyrates; 0/Ribonucleotides; 0/Vasoconstrictor Agents; 11089-65-9/Tunicamycin; 11128-99-7/Angiotensin II; 133407-82-6/benzyloxycarbonylleucyl-leucyl-leucine aldehyde; 360-97-4/Aminoimidazole Carboxamide; 516-35-8/Taurochenodeoxycholic Acid; 59-42-7/Phenylephrine; 60EUX8MN5X/tauroursodeoxycholic acid; 7WY7YBI87E/4-phenylbutyric acid; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.14.13.39/Nos3 protein, mouse; EC 2.7.11.1/AMP-Activated Protein Kinases; EC 2.7.11.1/AMPK alpha2 subunit, mouse; F0X88YW0YK/AICA ribonucleotide |
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