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1.
Free Radic Biol Med ; 53(2): 216-29, 2012 Jul 15.
Article in English | MEDLINE | ID: mdl-22583703

ABSTRACT

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.


Subject(s)
Acetylcarnitine/therapeutic use , Endothelial Cells/drug effects , GTP Cyclohydrolase/metabolism , Hypertension, Pulmonary/drug therapy , Proteasome Endopeptidase Complex/metabolism , Pulmonary Heart Disease/drug therapy , Adaptor Proteins, Signal Transducing/metabolism , Animals , Animals, Newborn , Arginine/analogs & derivatives , Arginine/pharmacology , Biopterins/analogs & derivatives , Biopterins/biosynthesis , Disease Models, Animal , Endothelial Cells/pathology , Female , HSP70 Heat-Shock Proteins/metabolism , Hypertension, Pulmonary/chemically induced , Hypertension, Pulmonary/surgery , Mitochondria/drug effects , Mitochondria/metabolism , Nitric Oxide/biosynthesis , Nitric Oxide Synthase/metabolism , Pregnancy , Proteasome Inhibitors/pharmacology , Pulmonary Artery/drug effects , Pulmonary Artery/pathology , Pulmonary Heart Disease/chemically induced , Pulmonary Heart Disease/surgery , Sheep , Signal Transduction , Ubiquitin-Protein Ligases/metabolism , Ubiquitination
2.
Vascul Pharmacol ; 53(1-2): 38-52, 2010.
Article in English | MEDLINE | ID: mdl-20362073

ABSTRACT

Although alterations in ROS generating systems are well described in several vascular disorders, there is very limited information on the perinatal regulation of these systems in the lung both during normal development and in pulmonary hypertension. Thus, this study was undertaken to explore how the two predominant superoxide generating systems, nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) and xanthine oxidase (XO), are developmentally regulated in control lambs and in our established lamb model of increased pulmonary blood flow (Shunt) over the first 2months of life. We found that the levels of p47(phox), p67(phox), and Rac1 subunits of NADPH oxidase complex were altered. During the first two months of life there was no change in p47(phox) protein levels in either normal or Shunt lambs. However, both p67(phox) and Rac1 protein levels decreased over time. In addition, p47(phox) protein levels were significantly increased in shunt lambs at 2- and 4-, but not 8-weeks of age compared to age-matched controls while levels of the p67(phox) subunit were decreased at 8-weeks of age in the Shunts but unchanged at other time periods. Furthermore, Rac1 protein expression was significantly increased in the Shunts only at 4weeks of age. These data correlated with a significant increase in NADPH oxidase dependent superoxide generation at 2- and 4-, but not 8-weeks of age in the Shunts. During normal development XO levels significantly increased over time in normal lambs but significantly decreased in the Shunts. In addition, XO protein levels were significantly increased in the Shunt at 2- and 4-weeks of age but significantly decreased at 8-weeks. Again this correlated with a significant increase in XO dependent superoxide generation at 2- and 4-, but not 8-weeks of age in the Shunts. Collectively, our findings suggest that NADPH oxidase and XO are major contributors to superoxide generation both during the normal development and during the development of pulmonary hypertension.


Subject(s)
Lung/metabolism , NADPH Oxidases/metabolism , Superoxides/metabolism , Xanthine Oxidase/metabolism , Age Factors , Animals , Female , Hypertension, Pulmonary/enzymology , Lung/enzymology , Lung/growth & development , Pregnancy , Pulmonary Circulation , Sheep , Time Factors , rac1 GTP-Binding Protein/metabolism
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