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Updated: Feb 25, 2026
Chronic Thromboembolic Pulmonary Hypertension and Assessment of Right Ventricular Function in the Piglet
Published on: November 4, 2015
Docetaxel Reverses Pulmonary Vascular Remodeling by Decreasing Autophagy and Resolves Right Ventricular Fibrosis
Yasmine F Ibrahim1, Nataliia V Shults1, Vladyslava Rybka1
1Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC (Y.F.I., N.V.S., V.R., Y.J.S.); and Department of Pharmacology, Minia University School of Medicine, Minia, Egypt (Y.F.I.).
Abstract:
Pulmonary arterial hypertension remains a fatal disease despite the availability of approved vasodilators. Since vascular remodeling contributes to increased pulmonary arterial pressure, new agents that reduce the thickness of pulmonary vascular walls have therapeutic potential. Thus, antitumor agents that are capable of killing cells were investigated. Testing of various antitumor drugs identified that docetaxel is a superior drug for killing proliferating pulmonary artery smooth muscle cells compared with other drugs, including gemcitabine, methotrexate, and ifosfamide. The administration of docetaxel to rats with severe pulmonary arterial hypertension reversed pulmonary vascular remodeling and reduced right ventricular pressure. Docetaxel was found to decrease autophagy as monitored by LC3B-II and p62 expression. The small interfering RNA knockdown of Beclin-1 or LC3B potentiated docetaxel-induced cell death, and knocking down p62 inhibited the docetaxel effects. The suppressed autophagic process is due to the ability of docetaxel to decrease Beclin-1 protein expression in a proteasome-dependent manner. Mass spectrometry identified a novel docetaxel-inducible Beclin-1 binding protein, namely, myosin-9. Knocking down myosin-9 inhibited docetaxel-induced cell death. In damaged right ventricles of pulmonary arterial hypertension rats, docetaxel remarkably promoted the resolution of fibrosis and the regeneration of myocardium. Thus, docetaxel is capable of reversing pulmonary vascular remodeling and resolving right ventricle fibrosis and is a promising therapeutic agent for the treatment of pulmonary arterial hypertension and right heart failure.
Insights
Docetaxel, an antitumor drug, effectively reverses pulmonary vascular remodeling and reduces right ventricular pressure in pulmonary arterial hypertension. It inhibits autophagy, promoting cell death and offering potential treatment for this fatal disease and right heart failure.
Area of Science:
- Cardiovascular Research
- Oncology
- Cell Biology
Background:
- Pulmonary arterial hypertension (PAH) is a fatal condition characterized by vascular remodeling and increased pulmonary arterial pressure.
- Current vasodilators are insufficient, necessitating novel therapeutic strategies targeting vascular wall thickening.
Purpose of the Study:
- To investigate the potential of antitumor agents in treating PAH by targeting proliferating pulmonary artery smooth muscle cells.
- To evaluate docetaxel's efficacy in reversing vascular remodeling and improving right ventricular function in a rat model of PAH.
Main Methods:
- Screening of various antitumor drugs for their ability to kill pulmonary artery smooth muscle cells.
- Administration of docetaxel to rats with induced pulmonary arterial hypertension.
- Assessment of docetaxel's effects on autophagy markers (LC3B-II, p62, Beclin-1) and cell death pathways.
- Identification of docetaxel-interacting proteins using mass spectrometry.
- Evaluation of docetaxel's impact on right ventricular fibrosis and myocardial regeneration.
Main Results:
- Docetaxel demonstrated superior efficacy in killing proliferating pulmonary artery smooth muscle cells compared to other tested antitumor agents.
- Docetaxel administration reversed pulmonary vascular remodeling, reduced right ventricular pressure, and alleviated right ventricle fibrosis in PAH rats.
- Docetaxel suppressed autophagy by decreasing Beclin-1 protein expression via a proteasome-dependent mechanism.
- Myosin-9 was identified as a novel docetaxel-inducible Beclin-1 binding protein, crucial for docetaxel-induced cell death.
Conclusions:
- Docetaxel is a promising therapeutic agent for pulmonary arterial hypertension, capable of reversing vascular remodeling and resolving right ventricle fibrosis.
- Docetaxel's mechanism involves the suppression of autophagy and interaction with myosin-9, leading to the death of pulmonary artery smooth muscle cells.
- Docetaxel holds potential for treating both pulmonary arterial hypertension and associated right heart failure.
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