Chloroquine in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a complex condition resulting from excess proliferation and impaired apoptosis of pulmonary artery smooth muscle cells (PASMCs), as well as vasoconstriction, inflammation, endothelial abnormalities, dysfunctional autophagy, and alterations in PASMC metabolism. Bone morphogenetic protein receptor II (BMPR-II) is the most common genetic abnormality in hereditary PAH and is also significantly reduced in both nonhereditary PAH and experimental PAH. The treatments currently available for PAH are primarily vasodilators, which have been shown to improve functional capacity and survival. However, despite these agents, PAH remains a fatal disease without curative therapies. In this study, Long et al examined the role of autophagy and BMPR-II degradation in experimental and human PAH. Previous work from this group identified that the decreased levels of BMPR-II in experimental models of PAH are due in part to degradation of BMPR-II by the lysosome. Therefore, they also studied the role of chloroquine, a long-established antimalarial drug and known inhibitor of autophagy, in experimental PAH. Long et al studied both human PASMCs and a well-established rat model of PAH to test the relationship among autophagy, lysosomal degradation of BMPR-II, PASMC proliferation/apoptosis, and the development of PAH. The authors used the monocrotaline rat model of PAH to study the use of chloroquine in both preventing and regressing PAH. After treatment with chloroquine, the animals were assessed with invasive hemodynamics, vascular staining for PASMC proliferation and apoptosis, as well as immunohistochemistry staining for lung p62 and LC3B-II expression, both markers …