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, 2013 Jul 05.
Article
em En
| MEDLINE
| ID: mdl-23652801
ABSTRACT
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 (Ca²âºm 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 Ca²âºm 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 ANDRESULTS:
Ucp2 knockout (KO)-PASMCs had lower mitochondrial calcium than Ucp2 wildtype (WT)-PASMCs at baseline and during histamine-stimulated ER-Ca²âº release. Normoxic Ucp2KO-PASMCs had mitochondrial hyperpolarization, lower Ca²âº-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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Artéria Pulmonar
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Proteínas Mitocondriais
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Estresse do Retículo Endoplasmático
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Hipertensão Pulmonar
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Canais Iônicos
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Hipóxia
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Mitocôndrias
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article