Abstract
We previously showed that tanshinone IIA ameliorated the hypoxia-induced pulmonary hypertension (HPH) partially by attenuating pulmonary artery remodeling. The hypoxia-induced proliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the major causes for pulmonary arterial remodeling, therefore the present study was performed to explore the effects and underlying mechanism of tanshinone IIA on the hypoxia-induced PASMCs proliferation. PASMCs were isolated from male Sprague-Dawley rats and cultured in normoxic (21%) or hypoxic (3%) condition. Cell proliferation was measured with 3 - (4, 5 - dimethylthiazal - 2 - yl) - 2, 5 - diphenyltetrazoliumbromide assay and cell counting. Cell cycle was measured with flow cytometry. The expression of of p27, Skp-2 and the phosphorylation of Akt were measured using western blot and/or RT-PCR respectively. The results showed that tanshinone IIA significantly inhibited the hypoxia-induced PASMCs proliferation in a concentration-dependent manner and arrested the cells in G1/G0-phase. Tanshinone IIA reversed the hypoxia-induced reduction of p27 protein, a cyclin-dependent kinase inhibitor, in PASMCs by slowing down its degradation. Knockdown of p27 with specific siRNA abolished the anti-proliferation of tanshinone IIA. Moreover, tanshinone IIA inhibited the hypoxia-induced increase of S-phase kinase-associated protein 2 (Skp2) and the phosphorylation of Akt, both of which are involved in the degradation of p27 protein. In vivo tanshinone IIA significantly upregulated the hypoxia-induced p27 protein reduction and downregulated the hypoxia-induced Skp2 increase in pulmonary arteries in HPH rats. Therefore, we propose that the inhibition of tanshinone IIA on hypoxia-induce PASMCs proliferation may be due to arresting the cells in G1/G0-phase by slowing down the hypoxia-induced degradation of p27 via Akt/Skp2-associated pathway. The novel information partially explained the anti-remodeling property of tanshinone IIA on pulmonary artery in HPH.
Highlights
Chronic hypoxia-induced pulmonary hypertension (HPH), characterized by the sustained pulmonary artery constriction and progressive structure remodeling, contributes to the morbidity and mortality of adult and pediatric patients with various lung and heart diseases [1]
The present study firstly demonstrated that tanshinone IIA modulated the hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) proliferation via Akt/S-phase kinase-associated protein 2 (Skp2)/p27associated pathway
The cell viability experiments showed that tanshinone IIA at 3, 10, 30 and 50 mg/mL had no significant cytotoxicity on PASMCs under both normoxic and hypoxic conditions
Summary
Chronic hypoxia-induced pulmonary hypertension (HPH), characterized by the sustained pulmonary artery constriction and progressive structure remodeling, contributes to the morbidity and mortality of adult and pediatric patients with various lung and heart diseases [1]. Pulmonary artery structure remodeling plays a key role in the persistent deterioration and the difficult reverse of HPH [1]. Current therapies mainly focus on altering the vasoconstrictive elements. There are few effective therapies to halt the progression of HPH [2]. One of the major causes for chronic hypoxia-induced pulmonary arterial remodeling is the aberrant proliferation of pulmonary artery smooth muscle cells (PASMCs) [3]. Inhibition of the aberrant proliferation of PASMCs may halt the deteriorative progress of HPH
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