Endothelin-1 induces a glycolytic switch in pulmonary arterial endothelial cells via the mitochondrial translocation of endothelial nitric oxide synthase.

Xutong Sun, Sanjiv Kumar, Shruti Sharma, Saurabh Aggarwal, Qing Lu, Christine Gross, Olga Rafikova, Sung Gon Lee, Sridevi Dasarathy, Yali Hou, Mary Louise Meadows, Weihong Han, Yunchao Su, Jeffrey R Fineman, Stephen M Black

Index: Am. J. Respir. Cell. Mol. Biol. 50(6) , 1084-95, (2014)

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Abstract

Recent studies have indicated that, during the development of pulmonary hypertension (PH), there is a switch from oxidative phosphorylation to glycolysis in the pulmonary endothelium. However, the mechanisms underlying this phenomenon have not been elucidated. Endothelin (ET)-1, an endothelial-derived vasoconstrictor peptide, is increased in PH, and has been shown to play an important role in the oxidative stress associated with PH. Thus, in this study, we investigated whether there was a potential link between increases in ET-1 and mitochondrial remodeling. Our data indicate that ET-1 induces the redistribution of endothelial nitric oxide synthase (eNOS) from the plasma membrane to the mitochondria in pulmonary arterial endothelial cells, and that this was dependent on eNOS uncoupling. We also found that ET-1 disturbed carnitine metabolism, resulting in the attenuation of mitochondrial bioenergetics. However, ATP levels were unchanged due to a compensatory increase in glycolysis. Further mechanistic investigations demonstrated that ET-1 mediated the redistribution of eNOS via the phosphorylation of eNOS at Thr495 by protein kinase C δ. In addition, the glycolytic switch appeared to be dependent on mitochondrial-derived reactive oxygen species that led to the activation of hypoxia-inducible factor signaling. Finally, the cell culture data were confirmed in vivo using the monocrotaline rat model of PH. Thus, we conclude that ET-1 induces a glycolytic switch in pulmonary arterial endothelial cells via the redistribution of uncoupled eNOS to the mitochondria, and that preventing this event may be an approach for the treatment of PH.