Uncoupling protein 2 deficiency mimics the effects of hypoxia and endoplasmic reticulum stress on mitochondria and triggers pseudohypoxic pulmonary vascular remodeling and pulmonary hypertension

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.

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.

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 pulmonary hypertension and exhibited a pseudohypoxic state with pulmonary vascular and systemic hypoxia inducible factor-1α 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.