1. Genetic knockout and pharmacologic inhibition of NCX1 attenuate hypoxia-induced pulmonary arterial hypertension
- Author
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Kohtaro Abe, Asahi Nagata, Satomi Kita, Tomo Kita, Naoko Nakajima, Hideaki Tagashira, Akinori Iwasaki, and Takahiro Iwamoto
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0301 basic medicine ,medicine.medical_specialty ,Vascular smooth muscle ,Biophysics ,Biochemistry ,Sodium-Calcium Exchanger ,Muscle hypertrophy ,Gene Knockout Techniques ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Internal medicine ,medicine ,Animals ,Hypoxia ,Molecular Biology ,Mice, Knockout ,Membrane potential ,Pulmonary Arterial Hypertension ,Aniline Compounds ,Chemistry ,Phenyl Ethers ,Cell Biology ,Hypoxia (medical) ,Pathophysiology ,Up-Regulation ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,030220 oncology & carcinogenesis ,cardiovascular system ,medicine.symptom ,Intracellular ,Homeostasis - 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.
- Published
- 2020
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