Docetaxel Reverses Pulmonary Vascular Remodeling by Decreasing Autophagy and Resolves Right Ventricular Fibrosis

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.

Effects of Bcl-2/Bcl-xL Inhibitors on Pulmonary Artery Smooth Muscle Cells

“…In the present study, the SU5416/hypoxia model with pathologic features similar to those in human PAH was used [ 12 , 13 , 14 , 17 , 18 , 19 , 20 ]. Male Sprague-Dawley CD rats and male Fischer CDF rats (Charles River Laboratories, Wilmington, MA, USA) were injected with 20 mg/kg bodyweight of SU5416 subcutaneously (MedChemExpress, Monmouth Junction, NJ, USA), subjected to sustained hypoxia for 3 weeks, and then maintained in normoxia.…”

“…Male Sprague-Dawley CD rats and male Fischer CDF rats (Charles River Laboratories, Wilmington, MA, USA) were injected with 20 mg/kg bodyweight of SU5416 subcutaneously (MedChemExpress, Monmouth Junction, NJ, USA), subjected to sustained hypoxia for 3 weeks, and then maintained in normoxia. For hypoxia, animals were placed in a chamber regulated by an OxyCycler Oxygen Profile Controller (BioSpherix, Redfield, NY, USA) to maintain 10% O 2 with an influx of N 2 gas [ 14 , 21 ]. After pulmonary hypertension and pulmonary vascular remodeling were developed, the rats were injected with ABT-263 intraperitoneally.…”

“…After pulmonary hypertension and pulmonary vascular remodeling were developed, the rats were injected with ABT-263 intraperitoneally. The dose of ABT-263 used was similar to that used for other cancer drugs in our previously published studies [ 12 , 13 , 14 ].…”

“…In this regard, our laboratory has established the concept of the apoptosis-based therapy to reverse pulmonary vascular remodeling to treat PAH patients [ 11 ]. In rat models of PAH, our laboratory discovered that anti-cancer agents including the anthracycline, proteasome inhibitor, and taxane classes of drugs reversed pulmonary vascular remodeling [ 12 , 13 , 14 ]. These drugs, however, were found to also affect autophagy for the regulation of cell death.…”

“…Thus, the mechanisms of action of these drugs involve autophagic cell death in addition to apoptotic cell death. On the other hand, a taxane anti-cancer drug, docetaxel, was found to inhibit autophagy, and the inhibition of autophagy enhanced the docetaxel-induced cell death [ 14 ]. Thus, docetaxel appears to kill pulmonary vascular cells by suppressing the survival role of autophagy since autophagy can serve as both a cell killing and cell survival mechanism [ 14 ].…”