title: Carfilzomib reverses pulmonary arterial hypertension.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, DC 20057, USA Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Xinhong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, DC 20057, USA Department of Pharmacology, Minia University School of Medicine, Minia 61111, Egypt.
authors.forename: Yasmine F
authors.initials: YF
authors.lastname: Ibrahim
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, DC 20057, USA.
authors.forename: Dividutta
authors.initials: D
authors.lastname: Das
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, DC 20057, USA.
authors.forename: Makhosazane
authors.initials: M
authors.lastname: Zungu-Edmondson
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, DC 20057, USA.
authors.forename: Nataliia V
authors.initials: NV
authors.lastname: Shults
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, DC 20057, USA ys82@georgetown.edu.
authors.forename: Yuichiro J
authors.initials: YJ
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib
keywords: Apoptosis; Carfilzomib; Proteasome inhibitor; Pulmonary heart disease; Pulmonary hypertension