Endothelial Uncoupling Protein 2 Regulates Mitophagy and Pulmonary Hypertension During Intermittent Hypoxia

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Abstract

Objectives—

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.

Approach and Results—

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.

Conclusions—

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.

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