Preserving mitochondrial function prevents the proteasomal degradation of GTP cyclohydrolase i

Shruti Sharma, Xutong Sun, Sanjiv Kumar, Ruslan Rafikov, Angela Aramburo, Gokhan Kalkan, Jing Tian, Imran Rehmani, Suphin Kallarackal, Jeffrey R. Fineman, Stephen M. Black

Research output: Contribution to journalArticle

15 Scopus citations

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 (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 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 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.

Original languageEnglish (US)
Pages (from-to)216-229
Number of pages14
JournalFree Radical Biology and Medicine
Volume53
Issue number2
DOIs
StatePublished - Jul 15 2012

Keywords

  • BH
  • CHIP
  • Free radicals
  • Hsp70
  • Hsp90
  • Mitochondrial dysfunction
  • Ubiquitination

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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    Sharma, S., Sun, X., Kumar, S., Rafikov, R., Aramburo, A., Kalkan, G., Tian, J., Rehmani, I., Kallarackal, S., Fineman, J. R., & Black, S. M. (2012). Preserving mitochondrial function prevents the proteasomal degradation of GTP cyclohydrolase i. Free Radical Biology and Medicine, 53(2), 216-229. https://doi.org/10.1016/j.freeradbiomed.2012.03.016