Paclitaxel alleviates monocrotaline-induced pulmonary arterial hypertension via inhibition of FoxO1-mediated autophagy.

Abstract

It has been demonstrated that activation of autophagy is involved in the development of pulmonary arterial hypertension (PAH). Recent studies have shown that cytosolic forkhead box protein O1 (FoxO1) activates autophagy in cancer cells. Paclitaxel has been found to potentially reverse PAH progression. However, the role of FoxO1 and the effects of paclitaxel on autophagy in the pathogenesis of PAH remain unknown. PAH was generated by intraperitoneal injection of monocrotaline (MCT) to rats. The right ventricular systolic pressure (RVSP), the right ventricle hypertrophy index (RV/LV+S), and the percentage of medial wall thickness (%MT) were used to detect the development of PAH. Hematoxylin and eosin staining was performed to measure pulmonary vascular remodeling. The protein level, phosphorylation, and nucleus translocation of FoxO1 and the levels of LC3A, LC3B, and Beclin-1 were examined by immunoblotting. The results showed that in spite of reduced expression of FoxO1, elevated phosphorylation of FoxO1 caused most of FoxO1 accumulating in cytosolic fraction in MCT-PAH rats. Autophagy was also activated in the MCT-PAH group. In cultured rat pulmonary arterial smooth muscle cells (PASMCs), knockdown of FoxO1 markedly blocked autophagy activation, indicating that elevation of cytosolic FoxO1 stimulates autophagy activation. Treatment of PAH rats with paclitaxel reduced FoxO1 phosphorylation and increased FoxO1 nuclear accumulation, despite increased FoxO1 expression, therefore suppressed autophagy, finally reduced elevated RVSP, RV/LV+S, and %MT in MCT-induced PAH. Taken together, paclitaxel inhibits pulmonary vascular remodeling by FoxO1-mediated autophagy suppression, suggesting that paclitaxel might be a novel therapeutic agent for the prevention and treatment of PAH.

• Authors: Wei Feng, Jian Wang, Xin Yan, Cui Zhai, Wenhua Shi, Qingting Wang, Qianqian Zhang, Manxiang Li
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 392 Issue 5 Pg. 605-613 (05 2019) ISSN: 1432-1912 [Electronic] Germany
• PMID: 30683943 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• Nerve Tissue Proteins
• Foxo1 protein, rat
• Monocrotaline
• Paclitaxel

Topics

• Animals
• Antihypertensive Agents (pharmacology, therapeutic use)
• Autophagy (drug effects)
• Cells, Cultured
• Lung (drug effects, pathology)
• Male
• Monocrotaline
• Myocytes, Smooth Muscle (drug effects, metabolism)
• Nerve Tissue Proteins (genetics, metabolism)
• Paclitaxel (pharmacology, therapeutic use)
• Pulmonary Arterial Hypertension (chemically induced, drug therapy, metabolism, physiopathology)
• Pulmonary Artery (cytology, drug effects, pathology)
• Rats, Sprague-Dawley