TY - JOUR
T1 - Dissecting molecular mechanisms underlying pulmonary vascular smooth muscle cell dedifferentiation in pulmonary hypertension
T2 - Role of mutated caveolin-1 (Cav1F92A)-bone marrow mesenchymal stem cells
AU - Yu, Wancheng
AU - Chen, Haiying
AU - Yang, Hongli
AU - Ding, Jie
AU - Xia, Peng
AU - Mei, Xu
AU - Wang, Lei
AU - Chen, Shuangfeng
AU - Zou, Chengwei
AU - Wang, Le xin
PY - 2019/10
Y1 - 2019/10
N2 - Pulmonary arterial hypertension (PAH) is characterised by remodelling in vascular smooth muscles, and switching from contractile (differentiated) to synthetic (dedifferentiated) phenotype. This study aimed to investigate the effect of a mutated caveolin-1 (Cav1F92A) gene from bone marrow mesenchymal stem cells (rBMSCs) on phenotypic switching in the smooth muscle cells during PAH. Methods: Human pulmonary smooth muscle cells (HPASMCs) were treated with monocrotaline (MCT,1 μM), and co-cultured with Cav1F92A gene modified rBMSCs (rBMSCs/Cav1F92A). The nitric oxide (NO) production, cell adhesion, cell viability and inflammatory cytokines expression in rBMSCs was measured to evaluate the survival rate of rBMSCs and the changes of inflammatory cytokines. The concentration of NO/cGMP (nitric oxide/Guanosine-3',5'-cyclic monophosphate), the tumour necrosis factor-alpha (TNF-α), transforming growth factor-beta1 (TGF-β1) mRNA, the expression of contractile smooth muscle cells (SMCs) phenotype markers (thrombospondin-1 and Matrix Gla protein, MGP), the synthetic SMCs phenotype markers (H-caldesmon and smooth muscle gene SM22 alpha, SM22α), cell migration and the morphological changes in rBMSCs/Cav1F92A co-cultured HPASMCs were investigated. Results: Cav1F92A increased NO concentration, cell adhesion, cell viability, anti-inflammatory cytokines interleukin-4 (IL-4), and interleukin-10 (IL-10), but decreased the inflammatory cytokines interleukin-1α (IL-1α), interferon-γ (INF-γ) and TNF-α expression in rBMSCs. rBMSCs/Cav1F92A activated the NO/cGMP, down-regulated TNF-α, TGF-β1, thrombospondin-1 and MGP expression, up-regulated SM22α and H-caldesmon expression, restored cell morphology, and inhibited cell migration in MCT treated HPASMCs. Conclusions: rBMSCs/Cav1F92A inhibits switching from contractile to synthetic phenotype in HPASMCs. It also inhibits migration and promotes morphological restoration of these cells. rBMSCs/Cav1F92A may be used as a therapeutic modality for PAH.
AB - Pulmonary arterial hypertension (PAH) is characterised by remodelling in vascular smooth muscles, and switching from contractile (differentiated) to synthetic (dedifferentiated) phenotype. This study aimed to investigate the effect of a mutated caveolin-1 (Cav1F92A) gene from bone marrow mesenchymal stem cells (rBMSCs) on phenotypic switching in the smooth muscle cells during PAH. Methods: Human pulmonary smooth muscle cells (HPASMCs) were treated with monocrotaline (MCT,1 μM), and co-cultured with Cav1F92A gene modified rBMSCs (rBMSCs/Cav1F92A). The nitric oxide (NO) production, cell adhesion, cell viability and inflammatory cytokines expression in rBMSCs was measured to evaluate the survival rate of rBMSCs and the changes of inflammatory cytokines. The concentration of NO/cGMP (nitric oxide/Guanosine-3',5'-cyclic monophosphate), the tumour necrosis factor-alpha (TNF-α), transforming growth factor-beta1 (TGF-β1) mRNA, the expression of contractile smooth muscle cells (SMCs) phenotype markers (thrombospondin-1 and Matrix Gla protein, MGP), the synthetic SMCs phenotype markers (H-caldesmon and smooth muscle gene SM22 alpha, SM22α), cell migration and the morphological changes in rBMSCs/Cav1F92A co-cultured HPASMCs were investigated. Results: Cav1F92A increased NO concentration, cell adhesion, cell viability, anti-inflammatory cytokines interleukin-4 (IL-4), and interleukin-10 (IL-10), but decreased the inflammatory cytokines interleukin-1α (IL-1α), interferon-γ (INF-γ) and TNF-α expression in rBMSCs. rBMSCs/Cav1F92A activated the NO/cGMP, down-regulated TNF-α, TGF-β1, thrombospondin-1 and MGP expression, up-regulated SM22α and H-caldesmon expression, restored cell morphology, and inhibited cell migration in MCT treated HPASMCs. Conclusions: rBMSCs/Cav1F92A inhibits switching from contractile to synthetic phenotype in HPASMCs. It also inhibits migration and promotes morphological restoration of these cells. rBMSCs/Cav1F92A may be used as a therapeutic modality for PAH.
KW - Human pulmonary artery smooth muscle cells
KW - Mutation caveolin-1(Cav1)
KW - Nitric oxide
KW - Phenotypic switching
KW - Rat bone marrow mesenchymal stem cells
UR - http://www.scopus.com/inward/record.url?scp=85053822194&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053822194&partnerID=8YFLogxK
U2 - 10.1016/j.hlc.2018.08.002
DO - 10.1016/j.hlc.2018.08.002
M3 - Article
C2 - 30262154
AN - SCOPUS:85053822194
VL - 28
SP - 1587
EP - 1597
JO - Heart Lung and Circulation
JF - Heart Lung and Circulation
SN - 1443-9506
IS - 10
ER -
