title: Preserving mitochondrial function prevents the proteasomal degradation of GTP cyclohydrolase I.
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.
authors.affiliation: Program in Pulmonary Vascular Disease, Vascular Biology Center, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.forename: Xutong
authors.initials: X
authors.lastname: Sun
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Kumar
authors.forename: Ruslan
authors.initials: R
authors.lastname: Rafikov
authors.forename: Angela
authors.initials: A
authors.lastname: Aramburo
authors.forename: Gokhan
authors.initials: G
authors.lastname: Kalkan
authors.forename: Jing
authors.initials: J
authors.lastname: Tian
authors.forename: Imran
authors.initials: I
authors.lastname: Rehmani
authors.forename: Suphin
authors.initials: S
authors.lastname: Kallarackal
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fineman
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
mesh_terms: D000108:Acetylcarnitine / Q000627:therapeutic use*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001708:Biopterins / Q000031:analogs & derivatives / Q000096:biosynthesis; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D005260:Female; D006136:GTP Cyclohydrolase / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000601:surgery; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011247:Pregnancy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D011660:Pulmonary Heart Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000601:surgery; D012756:Sheep; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018840:HSP70 Heat-Shock Proteins; D061988:Proteasome Inhibitors; D001708:Biopterins; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D000108:Acetylcarnitine; D001120:Arginine; D019001:Nitric Oxide Synthase; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D006136:GTP Cyclohydrolase; C003402:sapropterin