title: Bortezomib alleviates experimental pulmonary arterial hypertension.
abstract: Vascular remodeling and endothelial dysfunction are important pathogenic features of pulmonary arterial hypertension (PAH). There is a growing body of evidence that proteasome inhibitors may be beneficial in vascular diseases by inhibiting proliferation of vascular smooth muscle cells (VSMCs) and ameliorating endothelial dysfunction. Here, we evaluated whether bortezomib (BTZ) could alleviate hypoxia- and monocrotaline (MCT)-induced PAH. BTZ (at doses from 1 to 100 μg/kg, or a dose of 100 μg/kg) was administered to mice every other day for the last 2 weeks of a 5-week hypoxia (10% O(2)) period, or to rats once daily from Day 22 to Day 34 after MCT challenge, respectively. BTZ treatment substantially suppressed elevation of right ventricular (RV) systolic pressure, RV hypertrophy, and pulmonary vascular remodeling in hypoxia-exposed mice. Similarly, BTZ treatment inhibited RV hypertrophy and vascular remodeling in MCT-injected rats. Strikingly, BTZ rescued 70% of MCT-injected rats up to Day 60, along with a considerable reduction in RV systolic pressure and suppression of vascular remodeling, whereas, among MCT-injected rats not administered BTZ, there were no survivors by Day 41. BTZ significantly suppressed proliferation of pulmonary VSMCs in vivo and in vitro. Furthermore, BTZ increased not only endothelial nitric oxide (NO) synthase (eNOS), phosphorylated eNOS, and NO production in vitro, but also eNOS and p-eNOS in hypoxia-exposed mice and MCT-injected rats, respectively. In contrast to the beneficial effects, BTZ increased active caspase-3 in cardiac ventricles of MCT-injected rats. Taken together, with caution for cardiotoxicity, BTZ could be a potential therapeutic strategy in PAH, possibly acting by inhibition of VSMC proliferation and amelioration of endothelial dysfunction.
authors: Division of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, 300 Chunchun-dong, Jangan-gu, Suwon 440-746, Republic of Korea.
authors: Sun-Yong
authors: SY
authors: Kim
authors: Ji-Hyun
authors: JH
authors: Lee
authors: Jin Won
authors: JW
authors: Huh
authors: Hyo Jeong
authors: HJ
authors: Kim
authors: Mi Kyeong
authors: MK
authors: Park
authors: Jai Youl
authors: JY
authors: Ro
authors: Yeon-Mok
authors: YM
authors: Oh
authors: Sang-Do
authors: SD
authors: Lee
authors: Yun-Song
authors: YS
authors: Lee
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D004730:Endothelium, Vascular / Q000473:pathology; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016686:Monocrotaline; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D016686:Monocrotaline; D052250:Nitric Oxide Synthase Type III; C505410:Casp3 protein, rat; D053148:Caspase 3