Targeting CCL5 for Treatment of BMP-Mediated Pulmonary Hypertension

Abstract

Purpose Pulmonary arterial hypertension (PAH), a progressive disease characterized by progressive obliteration of small pulmonary arteries (PAs) that leads to elevated pulmonary arterial pressure and right heart failure. Most patients with severe PAH demonstrate persistent structural alterations in small PAs, including marked proliferation of pulmonary artery endothelial cells (PAECs), smooth muscle cells (PASMCs) and fibroblasts. Altered BMPR2 signaling is an essential piece in the pathobiologic puzzle of PAH. Reduced bone morphogenetic protein receptor 2 (BMPR2) expression in patients with PAH can impair pulmonary arterial endothelial cells (PAECs) function. This can adversely affect PAEC survival and promote PASMCs proliferation. We hypothesized that interventions to normalize the expression of genes that are targets of the BMPR2 signaling could restore PAECs function and prevent or reverse PAH. Methods Here have characterized for the first time, in human PAECs, chemokine (C-C motif) ligand 5 (CCL5/RANTES) deficiency restore bone morphogenetic protein (BMP)-mediated PAECs function. In cell culture experiments, we showed that CCL5 deficiency increased apoptosis and tube formation of PAECs, whereas it suppressed proliferation and migration of PASMCs. Results Silence the CCL5 expression in PAH PAECs restored BMP signaling responses, promoted phosphorylation of SMADs and transcription of ID genes. Moreover, CCL5 deficiency inhibited angiogenesis by increasing pSMAD-dependent and-independent BMPR2 signaling. This was linked mechanistically to enhanced interaction of BMPR2 with caveolin-1 via CCL5 deficiency-mediated stabilization of endothelial surface caveolin-1. Consistent with these functions, deletion of CCL5 significantly attenuated development of Sugen5416/hypoxia-induced PAH by restoring BMPR2 signaling in mice. Conclusion Taken together, our findings suggest that CCL5 deficiency could reverses obliterative changes in pulmonary arteries via caveolin-1-dependent amplification of BMPR2 signaling, shed a new light on our understanding of the disease pathobiology, and provides a possible novel therapeutic target for PAH. ADDIN EN.REFLIST.