Secreted Klotho Augments the Therapeutic Potential of Mesenchymal Stem Cells for Monocrotaline‐induced Pulmonary Arterial Hypertension

Abstract

ObjectiveKlotho is an anti‐aging gene. The purpose of this study is to investigate if secreted Klotho (SKL) in synergy with mesenchymal stem cells (MSCs) improves monocrotaline (MCT)‐induced pulmonary vascular dysfunction and pulmonary arterial hypertension (PAH).Methods & ResultsWe generated lentivirus carrying SKL‐GFP or GFP genes driven by a CMV promoter. MSCs were transfected with SKL‐GFP or GFP. Four groups of male rats were treated with MCT (60 mg/Kg, IP) while an additional group was given saline (control). Three days later, four MCT‐treated groups received IV delivery of MSCs, MSC‐GFP, MSC‐SKL‐GFP, and no treatment, respectively. MCT significantly increased right ventricular (RV) systolic blood pressure. Interestingly, MSC‐SKL‐GFP significantly attenuated the MCT‐induced increase in RV pressure (Saline 17.27 ± 4.86, MCT 31.88 ± 1.39, MCT + MSC‐SKL ‐GFP 23.35 ± 3.26). Ex vivo vascular relaxing responses to acetylcholine were decreased in small pulmonary arteries (PA) in MCT‐treated rats, indicating that MCT causes pulmonary vascular endothelial dysfunction. MSCs overexpressing SKL improved MCT‐induced PA endothelial dysfunction. MSC overexpressing SKL also significantly attenuated RV hypertrophy. MSCs alone, however, improved MCT‐induced PAH, PA endothelial dysfunction and RV hypertrophy but not to a significant level.ConclusionMSCs overexpressing SKL attenuated MCT‐induced PAH, PA endothelial dysfunction, and RV hypertrophy. SKL augments the therapeutic effect of MSCs in PAH.