| Preserving mitochondrial function prevents the proteasomal degradation of GTP cyclohydrolase I. | |
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MedLine Citation:
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PMID: 22583703 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-04-16 |
Journal Detail:
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Title: Free radical biology & medicine Volume: 53 ISSN: 1873-4596 ISO Abbreviation: Free Radic. Biol. Med. Publication Date: 2012 Jul |
Date Detail:
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Created Date: 2012-07-09 Completed Date: 2012-12-11 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 8709159 Medline TA: Free Radic Biol Med Country: United States |
Other Details:
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Languages: eng Pagination: 216-29 Citation Subset: IM |
Copyright Information:
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Copyright © 2012 Elsevier Inc. All rights reserved. |
Affiliation:
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Program in Pulmonary Vascular Disease, Vascular Biology Center, Georgia Health Sciences University, Augusta, GA 30912, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetylcarnitine
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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:
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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:
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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 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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