Document Detail


Preserving mitochondrial function prevents the proteasomal degradation of GTP cyclohydrolase I.
MedLine Citation:
PMID:  22583703     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The development of pulmonary hypertension is a common accompaniment of congenital heart disease (CHD) with increased pulmonary blood flow. Our recent evidence suggests that asymmetric dimethylarginine (ADMA)-induced mitochondrial dysfunction causes endothelial nitric oxide synthase (eNOS) uncoupling secondary to a proteasome-dependent degradation of GTP cyclohydrolase I (GCH1) that results in a decrease in the NOS cofactor tetrahydrobiopterin (BH(4)). Decreases in NO signaling are thought to be an early hallmark of endothelial dysfunction. As l-carnitine plays an important role in maintaining mitochondrial function, in this study we examined the protective mechanisms and the therapeutic potential of l-carnitine on NO signaling in pulmonary arterial endothelial cells and in a lamb model of CHD and increased pulmonary blood flow (Shunt). Acetyl-l-carnitine attenuated the ADMA-mediated proteasomal degradation of GCH1. This preservation was associated with a decrease in the association of GCH1 with Hsp70 and the C-terminus of Hsp70-interacting protein (CHIP) and a decrease in its ubiquitination. This in turn prevented the decrease in BH(4) levels induced by ADMA and preserved NO signaling. Treatment of Shunt lambs with l-carnitine also reduced GCH1/CHIP interactions, attenuated the ubiquitination and degradation of GCH1, and increased BH(4) levels compared to vehicle-treated Shunt lambs. The increases in BH(4) were associated with decreased NOS uncoupling and enhanced NO generation. Thus, we conclude that L-carnitine may have a therapeutic potential in the treatment of pulmonary hypertension in children with CHD with increased pulmonary blood flow.
Authors:
Shruti Sharma; Xutong Sun; Sanjiv Kumar; Ruslan Rafikov; Angela Aramburo; Gokhan Kalkan; Jing Tian; Imran Rehmani; Suphin Kallarackal; Jeffrey R Fineman; Stephen M Black
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-04-16
Journal Detail:
Title:  Free radical biology & medicine     Volume:  53     ISSN:  1873-4596     ISO Abbreviation:  Free Radic. Biol. Med.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-09     Completed Date:  2012-12-11     Revised Date:  2013-07-17    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  216-29     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Affiliation:
Program in Pulmonary Vascular Disease, Vascular Biology Center, Georgia Health Sciences University, Augusta, GA 30912, USA.
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MeSH Terms
Descriptor/Qualifier:
Acetylcarnitine / therapeutic use*
Adaptor Proteins, Signal Transducing / metabolism
Animals
Animals, Newborn
Arginine / analogs & derivatives,  pharmacology
Biopterin / analogs & derivatives,  biosynthesis
Disease Models, Animal
Endothelial Cells / drug effects*,  pathology
Female
GTP Cyclohydrolase / metabolism*
HSP70 Heat-Shock Proteins / metabolism
Hypertension, Pulmonary / chemically induced,  drug therapy*,  surgery
Mitochondria / drug effects,  metabolism
Nitric Oxide / biosynthesis
Nitric Oxide Synthase / metabolism
Pregnancy
Proteasome Endopeptidase Complex / metabolism*
Proteasome Inhibitors / pharmacology
Pulmonary Artery / drug effects,  pathology
Pulmonary Heart Disease / chemically induced,  drug therapy*,  surgery
Sheep
Signal Transduction
Ubiquitin-Protein Ligases / metabolism
Ubiquitination
Grant Support
ID/Acronym/Agency:
HL084739/HL/NHLBI NIH HHS; HL60190/HL/NHLBI NIH HHS; HL61284/HL/NHLBI NIH HHS; HL67841/HL/NHLBI NIH HHS; R01 HL060190/HL/NHLBI NIH HHS; R01 HL061284/HL/NHLBI NIH HHS; R01 HL067841/HL/NHLBI NIH HHS; R01 HL084739/HL/NHLBI NIH HHS; R21HD057406/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/HSP70 Heat-Shock Proteins; 0/Proteasome Inhibitors; 10102-43-9/Nitric Oxide; 14992-62-2/Acetylcarnitine; 17528-72-2/5,6,7,8-tetrahydrobiopterin; 22150-76-1/Biopterin; 30315-93-6/N,N-dimethylarginine; 74-79-3/Arginine; EC 1.14.13.39/Nitric Oxide Synthase; EC 3.4.25.1/Proteasome Endopeptidase Complex; EC 3.5.4.16/GTP Cyclohydrolase; EC 6.3.2.19/Ubiquitin-Protein Ligases
Comments/Corrections

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