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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
* Authors to whom correspondence should be addressed.
Received: 16 October 2012; in revised form: 26 November 2012 / Accepted: 30 November 2012 / Published: 21 December 2012
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
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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.
Sharma S, Sun X, Agarwal S, Rafikov R, Dasarathy S, Kumar S, Black SM. Role of Carnitine Acetyl Transferase in Regulation of Nitric Oxide Signaling in Pulmonary Arterial Endothelial Cells. International Journal of Molecular Sciences. 2013; 14(1):255-272.
Sharma, Shruti; Sun, Xutong; Agarwal, Saurabh; Rafikov, Ruslan; Dasarathy, Sridevi; Kumar, Sanjiv; Black, Stephen M. 2013. "Role of Carnitine Acetyl Transferase in Regulation of Nitric Oxide Signaling in Pulmonary Arterial Endothelial Cells." Int. J. Mol. Sci. 14, no. 1: 255-272.