Carfilzomib reverses pulmonary arterial hypertension.
Cardiovasc Res
; 110(2): 188-99, 2016 May 15.
Article
em En
| MEDLINE
| ID: mdl-26952044
ABSTRACT
AIMS:
Pulmonary arterial hypertension (PAH) remains a lethal disease with pronounced narrowing of pulmonary vessels due to abnormal cell growth. Agents that can reduce the pulmonary vascular thickness thus have therapeutic potential. The present study investigated the efficacy of carfilzomib (CFZ), a proteasome inhibitor and a cancer chemotherapeutic drug, on reversing PAH. METHODS ANDRESULTS:
In two rat models of PAH, SU5416/hypoxia and SU5416/ovalbumin, CFZ effectively reversed pulmonary vascular remodelling with the promotion of apoptosis and autophagy. In human pulmonary artery smooth muscle cells, knocking down mediators of autophagy attenuated CFZ-induced cell death. The cell death role of autophagy was promoted by the participation of tumour protein p53-inducible nuclear protein 1. CFZ increased the protein ubiquitination, and siRNA knockdown of ubiquitin inhibited cell death, suggesting that CFZ-induced cell death is ubiquitin-dependent. Mass spectrometry demonstrated the ubiquitination of major vault protein and heat shock protein 90 in response to CFZ. The siRNA knockdown of these proteins enhanced CFZ-induced cell death, revealing that they are cell survival factors. CFZ reduced right-ventricular pressure and enhanced the efficacy of a vasodilator, sodium nitroprusside. While no indications of CFZ toxicity were observed in the right ventricle of PAH rats, apoptosis was promoted in the left ventricle. Apoptosis was prevented by dexrazoxane or by pifithrin-α without interfering with the efficacy of CFZ to reverse pulmonary vascular remodelling.CONCLUSION:
The addition of anti-tumour agents such as CFZ along with cardioprotectants to currently available vasodilators may be a promising way to improve PAH therapy.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oligopeptídeos
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Proliferação de Células
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Inibidores de Proteassoma
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Hipertensão Pulmonar
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article