Olprinone modulates hypoxia-induced pulmonary vascular dysfunction: Underlying mechanisms and implications for circulatory homeostasis - 20/09/26
, Xiao-Wen Xu f, ⁎ , Guo-Xing Zhang g, ⁎ Abstract |
Backgrounds:
Chronic hypoxia-associated pulmonary hypertension (PH), especially COPD-related PH with right heart failure, is a recalcitrant clinical challenge as current therapies fail to effectively halt its progression. Olprinone (Olp), a phosphodiesterase III inhibitor with well-defined cardiovascular regulatory effects, has unclear roles and molecular mechanisms in hypoxia-induced PH.
Methods |
This study combined clinical, preclinical and cellular approaches: a retrospective analysis of 24 COPD-related PH patients (13 with Olp plus standard therapy, 11 with standard therapy plus other inotropes); a chronic hypoxia-induced PH (CHPH) rat model (10% O₂ for 4 weeks) treated with intraperitoneal Olp (0.2/0.4 mg/kg/d) for 2 weeks; hypoxic human pulmonary artery smooth muscle cells (HPASMCs, 3% O₂) exposed to Olp (30–300 nM), with IDH1 function validated by overexpression.
Results |
Clinically, Olp significantly reduced pulmonary artery systolic pressure (PASP) and serum NT-proBNP, and elevated the TAPSE/PASP ratio (a core right ventricular-pulmonary arterial coupling marker, all P < 0.05), with no significant changes in 6-minute walk distance or pulmonary function. In rats, Olp dose-dependently decreased mean PAP, RVSP and pulmonary artery medial thickening, and downregulated collagen I, α-SMA and PCNA (all P < 0.05 vs. hypoxia group). Olp suppressed hypoxic HPASMC proliferation, migration and invasion (P < 0.05), reduced IDH1 expression, and IDH1 overexpression completely reversed Olp’s protective effects on HPASMCs.
Conclusion |
Our findings suggest olprinone improves key right ventricular-pulmonary arterial coupling and pulmonary vascular remodeling in hypoxia-associated PH models, likely via regulating IDH1-related pathways. Clinical observations remain preliminary; further studies with COPD-PH models and prospective clinical trials are needed to confirm its therapeutic value.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Highlights |
• | Olprinone ameliorates hypoxia-induced pulmonary hypertension and optimizes right ventricular-pulmonary arterial coupling |
• | Olprinone inhibits abnormal proliferation and migration of hypoxic human pulmonary artery smooth muscle cells |
• | RNA-seq screening reveals IDH1 as a critical metabolic target mediating olprinone’s protective effects |
• | Olprinone blocks IDH1-α-KG signaling to restrain pulmonary vascular remodeling under chronic hypoxia |
Keywords : Olprinone, Pulmonary hypertension, Chronic hypoxia, Right ventricular function, IDH1
Plan
Vol 203
Article 119902- octobre 2026 Retour au numéro
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