Genetic knockout and pharmacologic inhibition of NCX1 attenuate hypoxia-induced pulmonary arterial hypertension.
Biochem Biophys Res Commun
; 529(3): 793-798, 2020 08 27.
Article
em En
| MEDLINE
| ID: mdl-32736709
ABSTRACT
The Na+/Ca2+ exchanger type-1 (NCX1) is a bidirectional transporter that is controlled by membrane potential and transmembrane gradients of Na+ and Ca2+. Vascular smooth muscle NCX1 plays an important role in intracellular Ca2+ homeostasis and Ca2+ signaling. We found that NCX1 was upregulated in the pulmonary arteries of mice exposed to chronic hypoxia (10% O2 for 4 weeks). Hence, we investigated the pathophysiological role of NCX1 in hypoxia-induced pulmonary arterial hypertension (PAH), using NCX1-heterozygous (NCX1+/-) mice, in which NCX1 expression is reduced by half, and SEA0400, a specific NCX1 inhibitor. NCX1+/- mice exhibited attenuation of hypoxia-induced PAH and right ventricular (RV) hypertrophy compared with wild-type mice. Furthermore, continuous administration of SEA0400 (0.5 mg/kg/day for 4 weeks) to wild-type mice by osmotic pumps significantly suppressed hypoxia-induced PAH and pulmonary vessel muscularization, with a slight reduction in RV hypertrophy. These findings indicate that the upregulation of NCX1 contributes to the development of hypoxia-induced PAH, suggesting that NCX1 inhibition might be a novel approach for the treatment of PAH.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Trocador de Sódio e Cálcio
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Hipertensão Arterial Pulmonar
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Hipóxia
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article