%0 Journal Article %A Nabham Rai %A Akylbek Sydykov %A Baktybek Kojonazarov %A Jochen Wilhelm %A Grégoire Manaud %A Swathi Veeroju %A Clemens Ruppert %A Frédéric Perros %A Hossein Ardeschir Ghofrani %A Norbert Weissmann %A Werner Seeger %A Ralph T. Schermuly %A Tatyana Novoyatleva %T Targeting peptidyl-prolyl isomerase 1 in experimental pulmonary arterial hypertension %D 2022 %R 10.1183/13993003.01698-2021 %J European Respiratory Journal %P 2101698 %X Pulmonary arterial hypertension (PAH) is a progressive disease characterised by pro-proliferative and anti-apoptotic phenotype in vascular cells, leading to pulmonary vascular remodelling and right heart failure. Peptidylprolyl cis/trans isomerase, NIMA interacting 1 (Pin1), a highly conserved enzyme, which binds to and catalyses the isomerisation of specific phosphorylated Ser/Thr-Pro motifs, acting as a molecular switch in multiple coordinated cellular processes. We hypothesised that Pin1 plays a substantial role in PAH and its inhibition with a natural organic compound, Juglone, would reverse experimental pulmonary hypertension (PH).We demonstrated that the expression of Pin1 was markedly elevated in experimental PH (i.e. hypoxia induced mouse and Sugen/hypoxia induced rat models) and pulmonary arterial smooth muscle cells (PASMCs) of patients with clinical PAH. In vitro Pin1 inhibition by either Juglone treatment or siRNA knock-down resulted in an induction of apoptosis and decrease in proliferation of human pulmonary vascular cells. Stimulation with growth factors induced Pin1 expression, while its inhibition reduced the activity of numerous PAH-related transcription factors, such as hypoxia-inducible factor alpha (HIF) and signal transducer and activator of transcription (STAT). Juglone administration lowered pulmonary vascular resistance, enhanced RV function, improved pulmonary vascular and cardiac remodelling in the Sugen/hypoxia rat model of PAH and the chronic hypoxia-induced PH model in mice.Our study demonstrates that targeting of Pin1 with small molecule inhibitor, Juglone, might be an attractive future therapeutic strategy for PAH and right heart disease secondary to PAH.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Rai has nothing to disclose.Conflict of interest: Dr. Sydykov has nothing to disclose.Conflict of interest: Dr. Kojonazarov has nothing to disclose.Conflict of interest: Dr. Wilhelm has nothing to disclose.Conflict of interest: Dr. Manaud has nothing to disclose.Conflict of interest: Dr. Veeroju has nothing to disclose.Conflict of interest: Dr. Ruppert has nothing to disclose.Conflict of interest: Dr. Frederic Perros has nothing to discloseConflict of interest: Dr. Ghofrani has nothing to disclose.Conflict of interest: Dr. Weissmann has nothing to disclose.Conflict of interest: Dr. Seeger reports personal fees from Actelion, personal fees from Bayer AG, personal fees from Novartis, personal fees from Vectura, personal fees from Medspray, personal fees from United Therapeutics, outside the submitted work;.Conflict of interest: Dr. Schermuly has nothing to disclose.Conflict of interest: Dr. Novoyatleva has nothing to disclose. %U https://erj.ersjournals.com/content/erj/early/2022/01/13/13993003.01698-2021.full.pdf