Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 53, Issue 2, Pages 216-229Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2012.03.016
Keywords
Mitochondrial dysfunction; BH4; Hsp90; Hsp70; CHIP; Ubiquitination; Free radicals
Funding
- National Institutes of Health [HL60190, HL67841, HL084739, R21HD057406, HL61284]
- Fondation Leducq
- Southeast Affiliates of the American Heart Association [09BGIA2310050]
- Cardiovascular Discovery Institute
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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 (BH4). 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 BH4 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 BH4 levels compared to vehicle-treated Shunt lambs. The increases in BH4 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. (C) 2012 Elsevier Inc. All rights reserved.
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