Baicalin inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation via the AKT/HIF-1α/p27-associated pathway.

Lin Zhang,Zhifeng Zhang,Dongmei Hu,Zhichen Pu,Junsong Wang,Junjie Wang

doi:10.3390/ijms15058153

Abstract

Baicalin, a flavonoid compound purified from the dry roots of Scutellaria baicalensis Georgi, has been shown to possess various pharmacological actions. Previous studies have revealed that baicalin inhibits the growth of cancer cells through the induction of apoptosis. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by enhanced pulmonary artery smooth muscle cell (PASMCs) proliferation and suppressed apoptosis. However, the potential mechanism of baicalin in the regulation of PASMC proliferation and the prevention of cardiovascular diseases remains unexplored. To test the effects of baicalin on hypoxia, we used rats treated with or without baicalin (100 mg·kg−1 each rat) at the beginning of the third week after hypoxia. Hemodynamic and pulmonary pathomorphology data showed that right ventricular systolic pressures (RVSP), the weight of the right ventricle/left ventricle plus septum (RV/LV + S) ratio and the medial width of pulmonary arterioles were much higher in chronic hypoxia. However, baicalin treatment repressed the elevation of RVSP, RV/LV + S and attenuated the pulmonary vascular structure remodeling (PVSR) of pulmonary arterioles induced by chronic hypoxia. Additionally, baicalin (10 and 20 μmol·L−1) treatment suppressed the proliferation of PASMCs and attenuated the expression of hypoxia-inducible factor-α (HIF-α) under hypoxia exposure. Meanwhile, baicalin reversed the hypoxia-induced reduction of p27 and increased AKT/protein kinase B phosphorylation p-AKT both in vivo and in vitro. These results suggested that baicalin could effectively attenuate PVSR and hypoxic pulmonary hypertension.

Highlights

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a sustained increase in pulmonary arterial pressure [1]
Cyclin-dependent kinases (CDKs) and CDK inhibitors regulate the balance between cell proliferation and cell quiescence [4]. p27, a CDK inhibitor, inhibits G1 cyclin/CDK complexes and blocks the G1-S transition in the cell cycle [5]. p27 blocks the cell cycle at the G0/G1 phase, which is a negative regulator of protein kinases, cyclin/CDK [6]
We found that a chronic hypoxia condition resulted in significantly elevated right ventricular systolic pressures (RVSP), increased the right ventricle/left ventricle plus septum (RV/LV + S) ratio and marked media thickening of pulmonary arterioles

Summary

Introduction

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a sustained increase in pulmonary arterial pressure [1]. Pulmonary vascular structure remodeling (PVSR) is a marker of severe and advanced PAH, which is partly due to the proliferation of pulmonary artery smooth muscle cells (PASMCs) [1,2,3]. The inhibition of the abnormal proliferation of PASMCs may open a new therapeutic window in PAH. Cyclin-dependent kinases (CDKs) and CDK inhibitors regulate the balance between cell proliferation and cell quiescence [4]. P27, a CDK inhibitor, inhibits G1 cyclin/CDK complexes and blocks the G1-S transition in the cell cycle [5]. P27 blocks the cell cycle at the G0/G1 phase, which is a negative regulator of protein kinases, cyclin/CDK [6]. In the normal cell cycle, the G0/G1-phase shows that p27 is much higher in expression. P27 is rapidly degraded, allowing the action of CDK2/cyclin E and CDK2/cyclin A to promote cell proliferation [7]

Results

Discussion

Conclusion