Baicalin Attenuates Hypoxia-Induced Pulmonary Arterial Hypertension to Improve Hypoxic Cor Pulmonale by Reducing the Activity of the p38 MAPK Signaling Pathway and MMP-9.

Shuangquan Yan,Ali Chen,Yiran Wang,Xiaomei Xu,Liangxing Wang,Dan Yao,Mayun Chen,Panpan Liu,Xiaoying Huang

doi:10.1155/2016/2546402

Abstract

Baicalin has a protective effect on hypoxia-induced pulmonary hypertension in rats, but the mechanism of this effect remains unclear. Thus, investigating the potential mechanism of this effect was the aim of the present study. Model rats that display hypoxic pulmonary hypertension and cor pulmonale under control conditions were successfully generated. We measured a series of indicators to observe the levels of pulmonary arterial hypertension, pulmonary arteriole remodeling, and right ventricular remodeling. We assessed the activation of p38 mitogen-activated protein kinase (MAPK) in the pulmonary arteriole walls and pulmonary tissue homogenates using immunohistochemistry and western blot analyses, respectively. The matrix metalloproteinase- (MMP-) 9 protein and mRNA levels in the pulmonary arteriole walls were measured using immunohistochemistry and in situ hybridization. Our results demonstrated that baicalin not only reduced p38 MAPK activation in both the pulmonary arteriole walls and tissue homogenates but also downregulated the protein and mRNA expression levels of MMP-9 in the pulmonary arteriole walls. This downregulation was accompanied by the attenuation of pulmonary hypertension, arteriole remodeling, and right ventricular remodeling. These results suggest that baicalin may attenuate pulmonary hypertension and cor pulmonale, which are induced by chronic hypoxia, by downregulating the p38 MAPK/MMP-9 pathway.

Highlights

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vasoconstriction and lung circulation remodeling, which can gradually elevate pulmonary vascular resistance, leading to right ventricular hypertrophy, dilatation, and dysfunction
The Matrix metalloproteinase- (MMP-)9 mRNA in situ hybridization (ISH) kit (MK1540) was purchased from Boster Biotechnology Co., Ltd. (Wuhan, China), and the rabbit antirat GAPDH antibody was obtained from Goodhere (China)
The Mean Pulmonary Artery Pressure (mPAP) was significantly higher in the hypoxia group than in the control group (25.12 ± 0.74 mmHg versus 16.94 ± 1.07 mmHg; P < 0.01), and the baicalin treatment remarkably reduced the mPAP to 17.50 ± 1.48 mmHg (P < 0.01) (Figures 1(a) and 1(c))

Summary

Introduction

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vasoconstriction and lung circulation remodeling, which can gradually elevate pulmonary vascular resistance, leading to right ventricular hypertrophy, dilatation, and dysfunction. Chronic hypoxic exposure can induce PAH, eventually leading to right ventricular hypertrophy and failure. Pulmonary arteriole remodeling, which includes smooth muscle cell proliferation, extracellular matrix (ECM) turnover, and collagen fiber accumulation, is the key step in this process [1]. Matrix metalloproteinase- (MMP-) 9 can participate in ECM turnover, fibrosis, and chronic inflammation, and MMP-9 promotes the proliferation of smooth muscle cells in blood vessels and their migration into the vessel wall [2, 3]. The same process occurs in the small pulmonary artery. As a member of the mitogen-activated protein kinase (MAPK) family, p38 MAPK can be activated by the phosphorylation of its subunits, and this activation plays an important role in inflammation and cell differentiation and proliferation in arteries [4, 5]

Methods

Results

Conclusion