A Defined Combination of Four Active Principles From the Danhong Injection Is Necessary and Sufficient to Accelerate EPC-Mediated Vascular Repair and Local Angiogenesis.

Shuang He,Yan Zhu,Xiumei Gao,Rongrong Chen,Miaomiao Jiang,Lanlan Pan,Jie Ren,Guanwei Fan,Gangjian Qin,Hao Guo,Yanzhi Meng,Tiechan Zhao

doi:10.3389/fphar.2019.01080

Abstract

Many compounds in Chinese medicine formulae, including Danhong injection (DHI) formulae, are capable of stimulating angiogenesis and promoting vascular repair, but their chemical basis and action mechanisms remain poorly defined. The aim of this study is to determine the minimal native chemical composition of DHI for the pro-angiogenesis activity and to evaluate its contribution from local endothelial cells (ECs) and bone marrow-derived endothelial progenitor cells (EPCs). Our study demonstrated that the action of DHI in accelerating the recovery of hindlimb blood flow in a ischemic rat model was attributable to its local CXCR4-mediated pro-angiogenesis activity in mature endothelial cells, as well as to its ability to promote the proliferation, migration, adhesion, and angiogenesis of EPCs via integrated activation of SDF-1α/CXCR4, VEGF/KDR, and eNOS/MMP-9 signal pathways. Combination experiments narrowed down the angiogenic activity into a few components in DHI. Reconstitution experiment defined that a combination of tanshinol, protocatechuic aldehyde, salvianolic acid B, and salvianolic acid C in their native proportion was necessary and sufficient for DHI’s angiogenic activity. Compared with the full DHI, the minimal reconstituted four active principles had the same effects in promoting tube formation in vitro, improving perfusion and recovery of ischemic limb, and enhancing angiogenesis in ischemic mice post-hindlimb ischemia in vivo.

Highlights

Cardiovascular and cerebrovascular ischemic diseases include a range of clinical syndromes induced by damage of vascular walls and are characterized by high morbidity, mortality, recurrence rate, and risk complications
In saline-treated rats, blood flow recovered to a ratio of 0.42 ± 0.06 after 7 days, whereas in DHItreated rats (0.25 ml/kg), the Laser Doppler perfusion imaging (LDPI) ratio was accelerated to 0.77 ± 0.07 after 7 days (Figure 1)
Our results showed that Danhong injection (DHI) promoted the expression of integrin αv which is related to the positive effect on the adhesion function of endothelial progenitor cells (EPCs). eNOS is a key enzyme in maintaining the endothelial functional integrality

Summary

Introduction

Cardiovascular and cerebrovascular ischemic diseases include a range of clinical syndromes induced by damage of vascular walls and are characterized by high morbidity, mortality, recurrence rate, and risk complications. These syndromes pose a serious health threat to humanity, especially to the elderly. Patients with cardiovascular and cerebrovascular diseases often require long-term medication for the treatment or prevention of recurrence. The development of effective and inexpensive drugs for the prevention and treatment of cardiovascular and cerebrovascular diseases will deliver substantial economic and social benefits to China and the world as a whole. Herbs play a role in improving the progression of CVD, in terms of platelet function, and have the potential to alter platelet function tests and some coagulation parameters (McEwen, 2015)

Objectives

Methods

Results

Discussion

Conclusion