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Publication
Endothelial uncoupling protein 2 regulates mitophagy and pulmonary hypertension
during intermittent hypoxia.
Authors Haslip M, Dostanic I, Huang Y, Zhang Y, Russell KS, Jurczak MJ, Mannam P,
Giordano F, Erzurum SC, Lee PJ
Submitted By Submitted Externally on 7/19/2018
Status Published
Journal Arteriosclerosis, thrombosis, and vascular biology
Year 2015
Date Published 5/1/2015
Volume : Pages 35 : 1166 - 78
PubMed Reference 25814675
Abstract Pulmonary hypertension (PH) is a process of lung vascular remodeling, which can
lead to right heart dysfunction and significant morbidity. The underlying
mechanisms leading to PH are not well understood, and therapies are limited.
Using intermittent hypoxia (IH) as a model of oxidant-induced PH, we identified
an important role for endothelial cell mitophagy via mitochondrial uncoupling
protein 2 (Ucp2) in the development of IH-induced PH., Ucp2 endothelial knockout
(VE-KO) and Ucp2 Flox (Flox) mice were subjected to 5 weeks of IH. Ucp2 VE-KO
mice exhibited higher right ventricular systolic pressure and worse right heart
hypertrophy, as measured by increased right ventricle weight/left ventricle plus
septal weight (RV/LV+S) ratio, at baseline and after IH. These changes were
accompanied by increased mitophagy. Primary mouse lung endothelial cells
transfected with Ucp2 siRNA and subjected to cyclic exposures to CoCl2 (chemical
hypoxia) showed increased mitophagy, as measured by PTEN-induced putative kinase
1 and LC3BII/I ratios, decreased mitochondrial biogenesis, and increased
apoptosis. Similar results were obtained in primary lung endothelial cells
isolated from VE-KO mice. Moreover, silencing PTEN-induced putative kinase 1 in
the endothelium of Ucp2 knockout mice, using endothelial-targeted lentiviral
silencing RNA in vivo, prevented IH-induced PH. Human pulmonary artery
endothelial cells from people with PH demonstrated changes similar to
Ucp2-silenced mouse lung endothelial cells., The loss of endothelial Ucp2 leads
to excessive PTEN-induced putative kinase 1-induced mitophagy, inadequate
mitochondrial biosynthesis, and increased apoptosis in endothelium. An
endothelial Ucp2-PTEN-induced putative kinase 1 axis may be effective
therapeutic targets in PH.




Strains




Genes
SymbolDescription
Ucp2uncoupling protein 2, mitochondrial

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