title: Lung-specific RNA interference of coupling factor 6, a novel peptide, attenuates pulmonary arterial hypertension in rats.
abstract: Pulmonary 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.
  
  
  
  PAH 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 (2×10(10) gp) was intratracheally transfected into the lungs of rats 2 weeks before or after MCT injection.
  
  
  
  A 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.
  
  
  
  CF6 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.
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Lixia District, Jinan, Shandong Province, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Pathology, Adicon Company, Wangkai Infectious Diseases Hospital of Zaozhuang City, Zaozhuang, Shandong, China.
authors.forename: Shuling
authors.initials: S
authors.lastname: You
authors.affiliation: Department of Emergency, Shandong Provincial Qianfoshan Hospital, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China.
authors.forename: Nannan
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Lixia District, Jinan, Shandong Province, China.
authors.forename: Shouhai
authors.initials: S
authors.lastname: Jiao
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Lixia District, Jinan, Shandong Province, China.
authors.forename: Hesheng
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Lixia District, Jinan, Shandong Province, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Xue
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Lixia District, Jinan, Shandong Province, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Lixia District, Jinan, Shandong Province, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong Province, China.
authors.forename: Ju
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Lixia District, Jinan, Shandong Province, China.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Lixia District, Jinan, Shandong Province, China. yansuhua5537@163.com.
authors.forename: Suhua
authors.initials: S
authors.lastname: Yan
authors.affiliation: Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Lixia District, Jinan, Shandong Province, China. lixiaolu007@hotmail.com.|Department of Emergency, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong Province, China. lixiaolu007@hotmail.com.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Li
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D015316:Genetic Therapy / Q000379:methods*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000628:therapy*; D007278:Injections, Spinal; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D016686:Monocrotaline; D020556:Neutrophil Infiltration; D010086:Oxidative Phosphorylation Coupling Factors / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D011651:Pulmonary Artery / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D066253:Vascular Remodeling; D018497:Ventricular Dysfunction, Right / Q000209:etiology / Q000235:genetics / Q000517:prevention & control
chemical_list: D010086:Oxidative Phosphorylation Coupling Factors; D034741:RNA, Small Interfering; D015121:6-Ketoprostaglandin F1 alpha; D016686:Monocrotaline; C000628217:F(6) ATPase; D025261:Mitochondrial Proton-Translocating ATPases
keywords: Coupling factor 6; Gene therapy; Prostacyclin; Pulmonary Hypertension