Qian Jiao1, Fangdi Zou2, Shiliang Li1, Jiawen Wang1, Yunping Xiao1, Zhihua Guan1, Liang Dong3, Jinwei Tian4, Shengqing Li3, Rui Wang1, Jian Zhang1,2, Honglin Li1. 1. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology Shanghai 200237, China. 2. School of Basic Medical Sciences, Tianjin Medical University Tianjin 200000, China. 3. Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan University Shanghai 200000, China. 4. Department of Cardiology, The Second Affiliated Hospital, Key Laboratory of Myocardial Ischemia, Harbin Medical University Harbin 200000, Heilongjiang, China.
Abstract
OBJECTIVES: To validate that dexlansoprazole, an anti-acid drug, can prevent pulmonary artery hypertension (PAH) in preclinical animal models and find the possible mechanism of action of dexlansoprazole for this new indication. METHODS: The efficacy of dexlansoprazole to attenuate PAH in vivo was evaluated in PAH animal models. Plasma guanosine 3', 5'-cyclic phosphate (cGMP) in PAH rats was measured by enzyme linked immunosorbent assay (ELISA). To investigate the anti-PAH effect of dexlansoprazole in vitro, proliferation and migration assays of primary cultured pulmonary artery smooth muscle cells (PASMCs) were performed. Furthermore, dexlansoprazole's function on fibroblast transition of vascular smooth muscle cells (VSMC) was explored by single cell ribonucleic acid (RNA) sequencing and RNAscope. RESULTS: Dexlansoprazole could attenuate the pathologic process in monocrotaline (MCT)-, hypoxia-induced PAH rats and SU5416/hypoxia (SuHy)-induced PAH mice. The intervention with dexlansoprazole significantly inhibited elevated right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary vascular wall thickness. Furthermore, plasma cGMP in MCT-induced PAH rats was restored after receiving dexlansoprazole. In vitro, dexlansoprazole could inhibit PASMCs' proliferation and migration stimulated by platelet derived growth factor-BB (PDGF-BB). Moreover, dexlansoprazole significantly ameliorated pulmonary vascular remodeling by inhibiting VSMC phenotypic transition to fibroblast-like cells in a VSMC-specific multispectral lineage-tracing mouse. CONCLUSIONS: Dexlansoprazole can prevent PAH through promoting cGMP generation and inhibiting pulmonary vascular remodeling through restraining PASMCs' proliferation, migration, and phenotypic transition to fibroblast-like cells. Consequently, PAH might be a new indication for dexlansoprazole. AJTR
OBJECTIVES: To validate that dexlansoprazole, an anti-acid drug, can prevent pulmonary artery hypertension (PAH) in preclinical animal models and find the possible mechanism of action of dexlansoprazole for this new indication. METHODS: The efficacy of dexlansoprazole to attenuate PAH in vivo was evaluated in PAH animal models. Plasma guanosine 3', 5'-cyclic phosphate (cGMP) in PAH rats was measured by enzyme linked immunosorbent assay (ELISA). To investigate the anti-PAH effect of dexlansoprazole in vitro, proliferation and migration assays of primary cultured pulmonary artery smooth muscle cells (PASMCs) were performed. Furthermore, dexlansoprazole's function on fibroblast transition of vascular smooth muscle cells (VSMC) was explored by single cell ribonucleic acid (RNA) sequencing and RNAscope. RESULTS: Dexlansoprazole could attenuate the pathologic process in monocrotaline (MCT)-, hypoxia-induced PAH rats and SU5416/hypoxia (SuHy)-induced PAH mice. The intervention with dexlansoprazole significantly inhibited elevated right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary vascular wall thickness. Furthermore, plasma cGMP in MCT-induced PAH rats was restored after receiving dexlansoprazole. In vitro, dexlansoprazole could inhibit PASMCs' proliferation and migration stimulated by platelet derived growth factor-BB (PDGF-BB). Moreover, dexlansoprazole significantly ameliorated pulmonary vascular remodeling by inhibiting VSMC phenotypic transition to fibroblast-like cells in a VSMC-specific multispectral lineage-tracing mouse. CONCLUSIONS: Dexlansoprazole can prevent PAH through promoting cGMP generation and inhibiting pulmonary vascular remodeling through restraining PASMCs' proliferation, migration, and phenotypic transition to fibroblast-like cells. Consequently, PAH might be a new indication for dexlansoprazole. AJTR
Authors: Jason C Kovacic; Stefanie Dimmeler; Richard P Harvey; Toren Finkel; Elena Aikawa; Guido Krenning; Andrew H Baker Journal: J Am Coll Cardiol Date: 2019-01-22 Impact factor: 24.094
Authors: Vallerie V McLaughlin; Stephen L Archer; David B Badesch; Robyn J Barst; Harrison W Farber; Jonathan R Lindner; Michael A Mathier; Michael D McGoon; Myung H Park; Robert S Rosenson; Lewis J Rubin; Victor F Tapson; John Varga; Robert A Harrington; Jeffrey L Anderson; Eric R Bates; Charles R Bridges; Mark J Eisenberg; Victor A Ferrari; Cindy L Grines; Mark A Hlatky; Alice K Jacobs; Sanjay Kaul; Robert C Lichtenberg; Jonathan R Lindner; David J Moliterno; Debabrata Mukherjee; Gerald M Pohost; Robert S Rosenson; Richard S Schofield; Samuel J Shubrooks; James H Stein; Cynthia M Tracy; Howard H Weitz; Deborah J Wesley Journal: Circulation Date: 2009-03-30 Impact factor: 29.690