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 Matthew Black

Research output: Contribution to journalArticle

14 Citations (Scopus)

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

Fingerprint

GTP Cyclohydrolase
Carnitine
Degradation
Ubiquitination
Pulmonary Hypertension
Blood
Lung
Heart Diseases
Acetylcarnitine
Pulmonary Heart Disease
Nitric Oxide Synthase Type III
Proteasome Endopeptidase Complex
Therapeutics
Endothelial cells
Proteins
Endothelial Cells
Association reactions
N,N-dimethylarginine

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Preserving mitochondrial function prevents the proteasomal degradation of GTP cyclohydrolase i. / Sharma, Shruti; Sun, Xutong; Kumar, Sanjiv; Rafikov, Ruslan; Aramburo, Angela; Kalkan, Gokhan; Tian, Jing; Rehmani, Imran; Kallarackal, Suphin; Fineman, Jeffrey R.; Black, Stephen Matthew.

In: Free Radical Biology and Medicine, Vol. 53, No. 2, 15.07.2012, p. 216-229.

Research output: Contribution to journalArticle

Sharma, S, Sun, X, Kumar, S, Rafikov, R, Aramburo, A, Kalkan, G, Tian, J, Rehmani, I, Kallarackal, S, Fineman, JR & Black, SM 2012, 'Preserving mitochondrial function prevents the proteasomal degradation of GTP cyclohydrolase i', Free Radical Biology and Medicine, vol. 53, no. 2, pp. 216-229. https://doi.org/10.1016/j.freeradbiomed.2012.03.016
Sharma, Shruti ; Sun, Xutong ; Kumar, Sanjiv ; Rafikov, Ruslan ; Aramburo, Angela ; Kalkan, Gokhan ; Tian, Jing ; Rehmani, Imran ; Kallarackal, Suphin ; Fineman, Jeffrey R. ; Black, Stephen Matthew. / Preserving mitochondrial function prevents the proteasomal degradation of GTP cyclohydrolase i. In: Free Radical Biology and Medicine. 2012 ; Vol. 53, No. 2. pp. 216-229.
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AU - Kalkan, Gokhan

AU - Tian, Jing

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