Chloroquine Prevents Progression of Experimental Pulmonary Hypertension via Inhibition of Autophagy and Lysosomal Bmpr-II Degradation
Rationale: Pulmonary arterial hypertension (PAH) is characterised by excessive proliferation and apoptosis resistance in pulmonary artery smooth muscle cells (PASMCs).
Objective: We reasoned that chloroquine, based on its ability to inhibit autophagy and block lysosomal degradation of the bone morphogenetic protein type II receptor (BMPR-II), might exert beneficial effects in this disease.
Methods and Results: PAH was induced in male Sprague-Dawley rats by administration of monocrotaline (MCT). The induction of PAH was associated with changes in lung expression of LC3B-II, ATG5 and p62, consistent with increased autophagy, and decreased BMPR-II protein expression. Administration of chloroquine prevented the development of PAH, right ventricular hypertrophy and vascular remodelling following MCT, and prevented progression of established PAH in this model. Similar results were obtained with hydroxychloroquine. Chloroquine treatment increased whole lung and PASMC p62 protein levels consistent with inhibition of autophagy, and increased levels of BMPR-II protein. Chloroquine inhibited proliferation and increased apoptosis of PASMCs in vivo. In cultured rat PASMCs we confirmed that chloroquine both inhibited autophagy pathways and increased expression of BMPR-II protein via lysosomal inhibition. Consistent with the in vivo findings, chloroquine inhibited the proliferation and stimulated apoptosis of rat PASMCs in vitro, with no effect on endothelial cell proliferation or survival. Moreover, direct inhibition of autophagy pathways by ATG5 siRNA knockdown inhibited proliferation of rat PASMCs.
Conclusions: Chloroquine and hydroxychloroquine exert beneficial effects in experimental PAH. The mechanism of action includes inhibition of autophagy pathways and inhibition of lysosomal degradation of BMPR-II.
- bone morphogenetic protein Type-II receptor
- pulmonary hypertension
- smooth muscle cell
- Received November 7, 2012.
- Revision received February 22, 2013.
- Accepted February 26, 2013.