| First Author | Dromparis P | Year | 2013 |
| Journal | Circ Res | Volume | 113 |
| Issue | 2 | Pages | 126-36 |
| PubMed ID | 23652801 | Mgi Jnum | J:213279 |
| Mgi Id | MGI:5584043 | Doi | 10.1161/CIRCRESAHA.112.300699 |
| Citation | Dromparis P, et al. (2013) Uncoupling protein 2 deficiency mimics the effects of hypoxia and endoplasmic reticulum stress on mitochondria and triggers pseudohypoxic pulmonary vascular remodeling and pulmonary hypertension. Circ Res 113(2):126-36 |
| abstractText | 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(2)(+)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 Ca(2)(+)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-1alpha 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-Ca(2)(+) release. Normoxic Ucp2KO-PASMCs had mitochondrial hyperpolarization, lower Ca(2)(+)-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 pulmonary hypertension and exhibited a pseudohypoxic state with pulmonary vascular and systemic hypoxia inducible factor-1alpha activation (increased hematocrit), not exacerbated further by chronic hypoxia. 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. |
