Uncoupling Protein 2 Deficiency Mimics the Effects of Hypoxia and Endoplasmic Reticulum Stress on Mitochondria and Triggers Pseudo-Hypoxic Pulmonary Vascular Remodeling and Pulmonary Hypertension
Rationale: Mitochondrial signaling regulates both the acute and chronic response of the pulmonary circulation to hypoxia, and suppressed mitochondrial glucose oxidation (GO) contributes to the apoptosis-resistance and proliferative diathesis in the vascular remodeling in pulmonary hypertension (PHT). Hypoxia directly inhibits GO, while endoplasmic reticulum (ER)-stress can indirectly inhibit GO 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 (HIF1α) activation and PHT.
Methods and Results: Ucp2KO-PASMCs had lower Ca2+m than Ucp2WT-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 PHT and exhibited a pseudo-hypoxic state with pulmonary vascular and systemic HIF1α activation (increased hematocrit), not exacerbated further by chronic hypoxia.
Conclusions: This first description of the role of UCP2 in oxygen sensing and in PHT vascular remodeling may open a new window in biomarker and therapeutic strategies.
- pulmonary vascular remodeling
- uncoupling protein
- pulmonary hypertension
- Received December 5, 2012.
- Revision received April 26, 2013.
- Accepted May 6, 2013.