Identification of Celastrol as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension and Right Ventricular Failure Through Suppression of Bsg (Basigin)/CyPA (Cyclophilin A)
| Autor: | Junichi Omura, Nobuhiro Kikuchi, Kimio Satoh, Tomohiko Shindo, Masamichi Nogi, Yutaro Takeuchi, Takashi Nakata, Shinichiro Sunamura, Mohammad Abdul Hai Siddique, Satoshi Miyata, Taijyu Satoh, Ryo Kurosawa, Hiroaki Shimokawa |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Indoles Ventricular Dysfunction Right Cypa Mice Transgenic 030204 cardiovascular system & hematology 03 medical and health sciences Cyclophilin A chemistry.chemical_compound Mice 0302 clinical medicine Fibrosis Internal medicine medicine.artery medicine Animals Humans Myocytes Cardiac Pyrroles Hypoxia Antihypertensive Agents Pulmonary Arterial Hypertension biology business.industry medicine.disease biology.organism_classification Pulmonary hypertension Triterpenes Rats Disease Models Animal 030104 developmental biology chemistry Celastrol Heart failure Basigin Pulmonary artery Cardiology Cardiology and Cardiovascular Medicine business Pentacyclic Triterpenes |
| Zdroj: | Arteriosclerosis, thrombosis, and vascular biology. 41(3) |
| ISSN: | 1524-4636 |
| Popis: | Objective:Pulmonary arterial hypertension is characterized by abnormal proliferation of pulmonary artery smooth muscle cells and vascular remodeling, which leads to right ventricular (RV) failure. Bsg (Basigin) is a transmembrane glycoprotein that promotes myofibroblast differentiation, cell proliferation, and matrix metalloproteinase activation. CyPA (cyclophilin A) binds to its receptor Bsg and promotes pulmonary artery smooth muscle cell proliferation and inflammatory cell recruitment. We previously reported that Bsg promotes cardiac fibrosis and failure in the left ventricle in response to pressure-overload in mice. However, the roles of Bsg and CyPA in RV failure remain to be elucidated.Approach and Results:First, we found that protein levels of Bsg and CyPA were upregulated in the heart of hypoxia-induced pulmonary hypertension (PH) in mice and monocrotaline-induced PH in rats. Furthermore, cardiomyocyte-specific Bsg-overexpressing mice showed exacerbated RV hypertrophy, fibrosis, and dysfunction compared with their littermates under chronic hypoxia and pulmonary artery banding. Treatment with celastrol, which we identified as a suppressor of Bsg and CyPA by drug screening, decreased proliferation, reactive oxygen species, and inflammatory cytokines in pulmonary artery smooth muscle cells. Furthermore, celastrol treatment ameliorated RV systolic pressure, hypertrophy, fibrosis, and dysfunction in hypoxia-induced PH in mice and SU5416/hypoxia-induced PH in rats with reduced Bsg, CyPA, and inflammatory cytokines in the hearts and lungs.Conclusions:These results indicate that elevated Bsg in pressure-overloaded RV exacerbates RV dysfunction and that celastrol ameliorates RV dysfunction in PH model animals by suppressing Bsg and its ligand CyPA. Thus, celastrol can be a novel drug for PH and RV failure that targets Bsg and CyPA.Graphic Abstract:A graphic abstract is available for this article. |
| Databáze: | OpenAIRE |
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