Document Detail


Phosphoinositide-dependent kinase-1 and protein kinase Cδ contribute to endothelin-1 constriction and elevated blood pressure in intermittent hypoxia.
MedLine Citation:
PMID:  23093023     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Obstructive sleep apnea (OSA) is associated with cardiovascular complications including hypertension. Previous findings from our laboratory indicate that exposure to intermittent hypoxia (IH), to mimic sleep apnea, increases blood pressure in rats. IH also increases endothelin-1 (ET-1) constrictor sensitivity in a protein kinase C (PKC) δ-dependent manner in mesenteric arteries. Because phosphoinositide-dependent kinase-1 (PDK-1) regulates PKCδ activity, we hypothesized that PDK-1 contributes to the augmented ET-1 constrictor sensitivity and elevated blood pressure following IH. Male Sprague-Dawley rats were exposed to either sham or IH (cycles between 21% O(2)/0% CO(2) and 5% O(2)/5% CO(2)) conditions for 7 h/day for 14 or 21 days. The contribution of PKCδ and PDK-1 to ET-1-mediated vasoconstriction was assessed in mesenteric arteries using pharmacological inhibitors. Constrictor sensitivity to ET-1 was enhanced in arteries from IH-exposed rats. Inhibition of PKCδ or PDK-1 blunted ET-1 constriction in arteries from IH but not sham group rats. Western analysis revealed similar levels of total and phosphorylated PDK-1 in arteries from sham and IH group rats but decreased protein-protein interaction between PKCδ and PDK-1 in arteries from IH- compared with sham-exposed rats. Blood pressure was increased in rats exposed to IH, and treatment with the PDK-1 inhibitor OSU-03012 [2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}-acetamide] (33 mg/day) lowered blood pressure in IH but not sham group rats. Our results suggest that exposure to IH unmasks a role for PDK-1 in regulating ET-1 constrictor sensitivity and blood pressure that is not present under normal conditions. These novel findings suggest that PDK-1 may be a uniquely effective antihypertensive therapy for OSA patients.
Authors:
Bradley R Webster; Jessica M Osmond; Daniel A Paredes; Xavier A DeLeon; Olan Jackson-Weaver; Benjimen R Walker; Nancy L Kanagy
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-23
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  344     ISSN:  1521-0103     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-12-24     Completed Date:  2013-02-26     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  68-76     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
3-Phosphoinositide-Dependent Protein Kinases
Animals
Anoxia / physiopathology*
Blood Pressure / drug effects*
Endothelin-1 / pharmacology*
Enzyme Inhibitors / pharmacology
Immunoprecipitation
Male
Mesenteric Arteries / drug effects
Phosphorylation
Protein Kinase C-delta / metabolism*
Protein-Serine-Threonine Kinases / antagonists & inhibitors,  metabolism*
Pyrazoles / pharmacology
Rats
Rats, Sprague-Dawley
Sleep Apnea Syndromes / complications,  physiopathology
Sulfonamides / pharmacology
Vasoconstriction / drug effects*
Grant Support
ID/Acronym/Agency:
HL07736/HL/NHLBI NIH HHS; HL82799/HL/NHLBI NIH HHS; HL95649/HL/NHLBI NIH HHS; R01 HL082799/HL/NHLBI NIH HHS; R25 GM060201/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Endothelin-1; 0/Enzyme Inhibitors; 0/OSU 03012; 0/Pyrazoles; 0/Sulfonamides; EC 2.7.11.1/3-Phosphoinositide-Dependent Protein Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.13/Protein Kinase C-delta
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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