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：Dromparis Peter; Paulin Roxane; Sutendra Gopinath; Qi Andrew C; Bonnet Sebastien; Michelakis Evangelos D^*

来源：Circulation Research, 2013, 113(2): 126-136.

DOI：10.1161/CIRCRESAHA.112.300699

• metabolism
• mitochondria
• pseudohypoxia
• pulmonary hypertension
• pulmonary vascular remodeling
• uncoupling protein

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 (Ca-m(2+) 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. %26lt;br%26gt;Objective: We hypothesized that UCP2 deficiency reduces Ca-m(2+) 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-1 activation and pulmonary hypertension. %26lt;br%26gt;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%26apos; cycle intermediates, and increased resistance to apoptosis, mimicking the hypoxia-induced changes in Ucp2WT-PASMC. Ucp2KO mice spontaneously developed pulmonary vascular remodeling and pulmonary hypertension and exhibited a pseudohypoxic state with pulmonary vascular and systemic hypoxia inducible factor-1 activation (increased hematocrit), not exacerbated further by chronic hypoxia. %26lt;br%26gt;Conclusions: This first description of the role of UCP2 in oxygen sensing and in pulmonary hypertension vascular remodeling may open a new window in biomarker and therapeutic strategies.

• 出版日期2013-7-5