Uncoupling Protein 2 Deficiency Mimics the Effects of Hypoxia and Endoplasmic Reticulum Stress on Mitochondria and Triggers Pseudohypoxic Pulmonary Vascular Remodeling and Pulmonary Hypertension

作者：Peter Dromparis, Roxane Paulin, Gopinath Sutendra, Andrew C. Qi, Sébastien Bonnet, Evangelos D. Michelakis · 发表于：Circulation Research · 年份：2013 · DOI：10.1161/circresaha.112.300699 · 被引用次数：144 · 研究领域：Pulmonary Hypertension Research and Treatments、Adipose Tissue and Metabolism、Cardiovascular Function and Risk Factors

RATIONALE: Mitochondrial signaling regulates both the acute and the chronic response of the pulmonary circulation to hypoxia, and suppressed mitochondrial glucose oxidation contributes to the apoptosis-resistance and proliferative diathesis in the vascular remodeling in pulmonary hypertension. Hypoxia directly inhibits glucose oxidation, whereas endoplasmic reticulum (ER)-stress can indirectly inhibit glucose oxidation by decreasing mitochondrial calcium (Ca²⁺m levels). Both hypoxia and ER stress promote proliferative pulmonary vascular remodeling. Uncoupling protein 2 (UCP2) has been shown to conduct calcium from the ER to mitochondria and suppress mitochondrial function. OBJECTIVE: We hypothesized that UCP2 deficiency reduces Ca²⁺m in pulmonary artery smooth muscle cells (PASMCs), mimicking the effects of hypoxia and ER stress on mitochondria in vitro and in vivo, promoting normoxic hypoxia inducible factor-1α activation and pulmonary hypertension. METHODS AND RESULTS: Ucp2 knockout (KO)-PASMCs had lower mitochondrial calcium than Ucp2 wildtype (WT)-PASMCs at baseline and during histamine-stimulated ER-Ca²⁺ release. Normoxic Ucp2KO-PASMCs had mitochondrial hyperpolarization, lower Ca²⁺-sensitive mitochondrial enzyme activity, reduced levels of mitochondrial reactive oxygen species and Krebs' cycle intermediates, and increased resistance to apoptosis, mimicking the hypoxia-induced changes in Ucp2WT-PASMC. Ucp2KO mice spontaneously developed pulmonary vascular remodeling and ...