Lung-specific RNA interference of coupling factor 6, a novel peptide, attenuates pulmonary arterial hypertension in rats

Abstract

BackgroundPulmonary arterial hypertension (PAH) is a progressive and life-threatening disease associated with high morbidity and mortality rates. However, the exact regulatory mechanism of PAH is unknown. Although coupling factor 6 (CF6) is known to function as a repressor, its role in PAH has not been explored. Here, we investigated the involvement of endogenous CF6 in the development of PAH.MethodsPAH was induced with monocrotaline (MCT), as demonstrated by significant increases in pulmonary artery pressure and vessel wall thickness. The adeno-associated virus (AAV) carrying CF6 short hairpin RNA (shRNA) or control vector (2×1010 gp) was intratracheally transfected into the lungs of rats 2 weeks before or after MCT injection.ResultsA 2-6-fold increase in CF6 was observed in the lungs and circulation of the MCT-injected rats as confirmed by qRT-PCR and ELISA. Immunohistochemistry analysis revealed a small quantity of CF6 localized to endothelial cells (ECs) under physiological conditions spread to surrounding tissues in a paracrine manner in PAH lungs. Notably, CF6 shRNA effectively inhibited CF6 expression, abolished lung macrophage infiltration, reversed endothelial dysfunction and vascular remodeling, and ameliorated the severity of pulmonary hypertension and right ventricular dysfunction at 4 weeks both as a pretreatment and rescue intervention. In addition, the circulating and lung levels of 6-keto-PGF1a, a stable metabolite of prostacyclin, were reversed by CF6 inhibition, suggesting that the effect of CF6 inhibition may partly be mediated through prostacyclin.ConclusionsCF6 contributes to the pathogenesis of PAH, probably in association with downregulation of prostacyclin. The blockage of CF6 might be applied as a novel therapeutic approach for PAH and PA remodeling.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0409-5) contains supplementary material, which is available to authorized users.

Role of P2X7R in the development and progression of pulmonary hypertension

“…The poor prognosis of patients afflicted by this disease despite treatment with currently available vasodilator drugs makes the development of new treatment strategies imperative. If vascular remodelling can be developed from redundant mediators, a combination “cocktail” consisting of anti-remodelling agents such as endothelin inhibitors, prostacyclin, and anti-inflammatory agents such as A-740003 may be more beneficial for patients with PAH than any single agent alone [ 55 ].…”

Impact of ATP synthase/coupling factor 6 in hypoxic pulmonary arterial hypertension: An experimental rat model

“…In addition, the levels of CF6 have been shown to markedly increase in rats with lung disease [ 11 , 12 ]. Our previous experiments have also demonstrated that CF6 was increased in monocrotaline (MCT)-induced PAH and that the inhibition of CF6 alleviated PA remodeling in rats [ 13 ]. These results demonstrated the critical role of CF6 in the pathogenesis of MCT-PAH.…”