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Int. J. Mol. Sci. 2013, 14(1), 255-272; doi:10.3390/ijms14010255

Role of Carnitine Acetyl Transferase in Regulation of Nitric Oxide Signaling in Pulmonary Arterial Endothelial Cells

Pulmonary Vascular Disease Program, Vascular Biology Center, 1459 Laney Walker Blvd, Georgia Health Sciences University, Augusta, GA 30912, USA
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Received: 16 October 2012 / Revised: 26 November 2012 / Accepted: 30 November 2012 / Published: 21 December 2012
(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)
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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.
Keywords: carnitine acetyl transferase; superoxide dismutase; nitric oxide; peroxynitrite; endothelial nitric oxide synthase carnitine acetyl transferase; superoxide dismutase; nitric oxide; peroxynitrite; endothelial nitric oxide synthase
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Sharma, S.; Sun, X.; Agarwal, S.; Rafikov, R.; Dasarathy, S.; Kumar, S.; Black, S.M. Role of Carnitine Acetyl Transferase in Regulation of Nitric Oxide Signaling in Pulmonary Arterial Endothelial Cells. Int. J. Mol. Sci. 2013, 14, 255-272.

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