Role of carnitine acetyl transferase in regulation of nitric oxide signaling in pulmonary arterial endothelial cells

Shruti Sharma, Xutong Sun, Saurabh Agarwal, Ruslan Rafikov, Sridevi Dasarathy, Sanjiv Kumar, Stephen M. Black

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Congenital heart defects with increased pulmonary blood flow (PBF) result in pulmonary endothelial dysfunction that is dependent, at least in part, on decreases in nitric oxide (NO) signaling. Utilizing a lamb model with left-to-right shunting of blood and increased PBF that mimics the human disease, we have recently shown that a disruption in carnitine homeostasis, due to a decreased carnitine acetyl transferase (CrAT) activity, correlates with decreased bioavailable NO. Thus, we undertook this study to test the hypothesis that the CrAT enzyme plays a major role in regulating NO signaling through its effect on mitochondrial function. We utilized the siRNA gene knockdown approach to mimic the effect of decreased CrAT activity in pulmonary arterial endothelial cells (PAEC). Our data indicate that silencing the CrAT gene disrupted cellular carnitine homeostasis, reduced the expression of mitochondrial superoxide dismutase-and resulted in an increase in oxidative stress within the mitochondrion. CrAT gene silencing also disrupted mitochondrial bioenergetics resulting in reduced ATP generation and decreased NO signaling secondary to a reduction in eNOS/Hsp90 interactions. Thus, this study links the disruption of carnitine homeostasis to the loss of NO signaling observed in children with CHD. Preserving carnitine homeostasis may have important clinical implications that warrant further investigation.

Original languageEnglish (US)
Pages (from-to)255-272
Number of pages18
JournalInternational journal of molecular sciences
Volume14
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • Carnitine acetyl transferase
  • Endothelial nitric oxide synthase
  • Nitric oxide
  • Peroxynitrite
  • Superoxide dismutase

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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