Abstract
Pulmonary arterial hypertension (PAH) is a serious condition. However, prevailing therapeutic strategies are not effective enough to treat PAH. Therefore, finding an effective therapy is clearly warranted. Adipose-derived mesenchymal stem cells (ASCs) and ASCs-derived exosomes (ASCs-Exos) exert protective effects in PAH, but the underlying mechanism remains unclear. Using a coculture of ASCs and monocrotaline pyrrole (MCTP)-treated human pulmonary artery endothelial cells (HPAECs), we demonstrated that ASCs increased cell proliferation in MCTP-treated HPAECs. Results showed that ASCs-Exos improved proliferation of both control HPAECs and MCTP-treated HPAECs. In addition, by transfecting ASCs with antagomir we observed that low exosomal miR-191 expression inhibited HPAECs proliferation whereas the agomir improved. Similar results were observed in vivo using a monocrotaline (MCT)-induced PAH rat model following ASCs transplantation. And ASCs transplantation attenuated MCT-induced PAH albeit less than the antagomir treated group. Finally, we found that miR-191 repressed the expression of bone morphogenetic protein receptor 2 (BMPR2) in HPAECs and PAH rats. Thus, we conjectured that miR-191, in ASCs and ASCs-Exos, plays an important role in PAH via regulation of BMPR2. These findings are expected to contribute to promising therapeutic strategies for treating PAH in the future.
Highlights
It is considered to be pulmonary arterial hypertension (PAH) when the mean pulmonary artery pressure is above 25 mmHg at rest [1]
Fluorescence-activated cell sorting (FACS) analysis showed that cell surface markers CD90 and CD105 were highly expressed while CD31 and CD45 staining was not observed in Adipose-derived mesenchymal stem cells (ASCs) (Figure 1(a))
Our study showed that inhibition of miR-191 could ameliorate the development of MCT-induced PAH possibly via preventing bone morphogenetic protein receptor 2 (BMPR2) degradation
Summary
It is considered to be pulmonary arterial hypertension (PAH) when the mean pulmonary artery pressure (mPAP) is above 25 mmHg at rest [1]. Pulmonary vascular resistance increases, leading to right heart failure and mortality [2]. Vascular remodeling is the key pathological feature of PAH, characterized by endothelial dysfunction, activation of fibroblasts, and smooth muscle cells. Endothelial dysfunction included suppression of normal apoptosis and excessive proliferation of endothelial cells [3]. The modern therapy has improved clinical state and extended life by a few years, but the vascular changes remain progressive [4]. No effective therapy that can either terminate or reverse the hyperplasia of human pulmonary artery endothelial cells (HPAECs) is available
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