Document Detail


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.
MedLine Citation:
PMID:  23288166     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Bin Liang; Shuangxi Wang; Qilong Wang; Wencheng Zhang; Benoit Viollet; Yi Zhu; Ming-Hui Zou
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-03
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  33     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-14     Completed Date:  2013-04-10     Revised Date:  2013-08-30    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  595-604     Citation Subset:  IM    
Affiliation:
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:
AMP-Activated Protein Kinases / 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:
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:
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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