Related Experiment Video
Updated: Aug 22, 2025
Establishment and Validation of a Rat Model of Pulmonary Arterial Hypertension Associated with Pulmonary Fibrosis
Published on: May 23, 2025
The Novel Lysosomal Autophagy Inhibitor (ROC-325) Ameliorates Experimental Pulmonary Hypertension
Changlei Bao1,2, Shuxin Liang1, Ying Han3
1State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, China (C.B., S.L., Z.Y., S.L., Y.S., S.Z., Y.L., K.W., J.W., H.T.).
Background:
Autophagy plays an important role in the pathogenesis of pulmonary hypertension (PH). ROC-325 is a novel small molecule lysosomal autophagy inhibitor that has more potent anticancer activity than the antimalarial drug hydroxychloroquine, the latter has been prevalently used to inhibit autophagy. Here, we sought to determine the therapeutic benefit and mechanism of action of ROC-325 in experimental PH models.
Methods And Results:
Hemodynamics, echocardiography, and histology measurement showed that ROC-325 treatment prevented the development of PH, right ventricular hypertrophy, fibrosis, dysfunction, and vascular remodeling after monocrotaline and Sugen5416/hypoxia administration. ROC-325 attenuated high K+ or alveolar hypoxia-induced pulmonary vasoconstriction and enhanced endothelial-dependent relaxation in isolated pulmonary artery rings. ROC-325 treatment inhibited autophagy and enhanced endothelial nitric oxide synthase activity in lung tissues of monocrotaline-PH rats. In cultured human and rat pulmonary arterial smooth muscle cell and pulmonary arterial endothelial cell under hypoxia exposure, ROC-325 increased LC3B (light chain 3 beta) and p62 accumulation, endothelial cell nitric oxide production via phosphorylation of endothelial nitric oxide synthase (Ser1177) and dephosphorylation of endothelial nitric oxide synthase (Thr495) as well as decreased HIF (hypoxia-inducible factor)-1α and HIF-2α stabilization.
Conclusions:
These data indicate that ROC-325 is a promising novel agent for the treatment of PH that inhibits autophagy, downregulates HIF levels, and increases nitric oxide production.
Insights
ROC-325, a novel autophagy inhibitor, shows therapeutic potential for pulmonary hypertension (PH). It prevents PH development and improves vascular function by inhibiting autophagy and enhancing nitric oxide production.
Area of Science:
- Pulmonary Hypertension Research
- Autophagy Inhibition
- Vascular Biology
Background:
- Autophagy is implicated in the pathogenesis of pulmonary hypertension (PH).
- ROC-325 is a novel small molecule lysosomal autophagy inhibitor with potent anticancer activity.
- Hydroxychloroquine, a common autophagy inhibitor, has been used to treat PH.
Purpose of the Study:
- To evaluate the therapeutic benefit of ROC-325 in experimental PH models.
- To elucidate the mechanism of action of ROC-325 in PH treatment.
Main Methods:
- ROC-325 treatment in monocrotaline and Sugen5416/hypoxia-induced PH models.
- Hemodynamic, echocardiographic, and histological assessments.
- In vitro studies on pulmonary arterial smooth muscle and endothelial cells under hypoxia.
Main Results:
- ROC-325 prevented PH development, right ventricular hypertrophy, fibrosis, and vascular remodeling.
- ROC-325 attenuated pulmonary vasoconstriction and enhanced endothelial-dependent relaxation.
- ROC-325 inhibited autophagy, increased nitric oxide production, and decreased HIF stabilization in lung tissues and cells.
Conclusions:
- ROC-325 is a promising agent for treating PH.
- ROC-325 acts by inhibiting autophagy, downregulating HIF levels, and increasing nitric oxide production.
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