Qingda Granule Attenuates Angiotensin II-Induced Blood Pressure and Inhibits Ca2+/ERK Signaling Pathway.

Meizhu Wu,Jun Peng,Lihui Wei,Aling Shen,Jiapeng Li,Jianfeng Chu,Liya Liu,Qiurong Xie,Qiaoyan Cai,Linzi Long,Xiaoping Chen,Zhiqing Shen,Xiangyan Wu,Ying Cheng

doi:10.3389/fphar.2021.688877

Abstract

Objective: As a well-known traditional Chinese medicine formula prescribed by academician Ke-ji Chen, Qingda granule (QDG) lowered the blood pressure of spontaneously hypertensive rats and attenuated hypertensive cardiac remodeling and inflammation. However, its functional role and underlying mechanisms on hypertensive vascular function remain largely unclear. This study aims to assess the effects of QDG treatment on Angiotensin II- (AngII-) induced hypertension and vascular function and explore its underlying mechanisms both in vitro and in vivo.Methods: In an in vivo study, 25 male C57BL/6 mice were randomly divided into five groups, including Control, AngII, AngII + QDG-L, AngII + QDG-M, and AngII + QDG-H groups (n = 5 for each group). Mice in AngII and AngII + QDG-L/-M/-H groups were infused with AngII (500 ng/kg/min), while in the Control group, they were infused with saline. Mice in AngII + QDG were intragastrically given different concentrations of QDG (0.5725, 1.145, or 2.29 g/kg/day), while in Control and AngII groups, they were intragastrically given equal volumes of double distilled water for 2 weeks. Blood pressure was determined at 0, 1, and 2 weeks of treatment. Ultrasound was used to detect the pulse wave velocity (PWV) and HE staining to detect the pathological change of the abdominal aorta. RNA sequencing (RNA-seq) was performed to identify the differentially expressed transcripts (DETs) and related signaling pathways. IHC was used to detect the expression of p-ERK in the abdominal aorta. Primary isolated rat vascular smooth muscle cells (VSMCs) were used to assess the cellular Ca2+ release and activation of the ERK pathway by confocal microscope and western blotting analysis, respectively.Results: QDG treatment significantly alleviated the elevated blood pressure, the PWV, and the thickness of the abdominal aorta in AngII-induced hypertensive mice. RNA-seq and KEGG analyses identified 1,505 DETs and multiple enriched pathways (including vascular contraction and calcium signaling pathway) after QDG treatment. Furthermore, confocal microscope showed that QDG treatment partially attenuated the increase of Ca2+ release with the stimulation of AngII in cultured VSMCs. In addition, IHC and western blotting indicated that QDG treatment also partially alleviated the increase of phospho-ERK levels in abdominal aorta tissues of mice and cultured VSMCs after the infusion or stimulation of AngII.Conclusion: QDG treatment attenuated the elevation of blood pressure, abdominal aorta dysfunction, pathological changes, Ca2+ release, and activation of the ERK signaling pathway.

Highlights

Hypertension is the most important modifiable risk factor for allcause morbidity and mortality worldwide and associated with an increased risk of cardiovascular diseases such as coronary artery disease, stroke, heart failure, and chronic kidney disease, which are the leading causes of death in China (Wenzel et al, 2011; Wang et al, 2018; Benjamin et al, 2019)
The blood pressure, including systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), was increased in angiotensin II (AngII)-infused mice, which was reversed by different concentrations of Qingda granule (QDG) treatment (Figures 1A–C), while no difference was found between different concentrations of QDG treatment
There was no significant difference in body weight among all groups (Figure 1D). These results suggest that QDG treatment lowers the blood pressure of AngII-induced hypertensive mice and didn’t affect body weight

Summary

Introduction

Hypertension is the most important modifiable risk factor for allcause morbidity and mortality worldwide and associated with an increased risk of cardiovascular diseases such as coronary artery disease, stroke, heart failure, and chronic kidney disease, which are the leading causes of death in China (Wenzel et al, 2011; Wang et al, 2018; Benjamin et al, 2019). The main damage of hypertension is that the long-term pressure overload causes the functional and structural change of the target organs, including the aorta, heart, and kidney, which causes organ failure (Touyz 2005; Rubattu et al, 2019; Di Palo and Barone, 2020). The RAAS has wide-ranging effects on blood pressure regulation, mediating vasoconstriction, endothelial dysfunction, and vascular injury through its most pharmacological factor angiotensin II (AngII) binding with its receptor, that is, AngII type I receptor (AT1R) (Gasc et al, 1994; Garg and Yusuf, 1995; Touyz 2005; Montezano et al, 2014). Rescuing the vascular functional and structural change at the early stage of hypertension may be an important means to interfere with the progression of hypertension

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Conclusion