Astragaloside IV Stimulates Angiogenesis and Increases Hypoxia-Inducible Factor-1α Accumulation via Phosphatidylinositol 3-Kinase/Akt Pathway

Abstract

Astragaloside IV is the major active constituent of Astragalus membranaceus, which has been widely used for the treatment of cardiovascular diseases in China. The aim of this study was to determine the angiogenic effect of astragaloside IV and its underlying mechanism. We used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay, Western blotting, real-time polymerase chain reaction, and immunofluorescence to detect the effect of astragaloside IV on proliferation of human umbilical vein endothelial cells (HUVECs), the phospho-Akt protein level, hypoxia-inducible factor-1␣ (HIF-1␣) accumulation, vascular endothelial growth factor mRNA expression, and applied cell migration, tube formation, and chick chorioallantoic membrane assays to study the angiogenic effect of astragaloside IV. Results indicate that astragaloside IV promoted cell proliferation and stimulated HIF-1␣ accumulation during hypoxia. Mechanism studies revealed that astragaloside IV did not affect the degradation of HIF-1␣ protein or the level of HIF-1␣ mRNA. In contrast, astragaloside IV apparently activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which regulates HIF-1␣ protein synthesis. Moreover, astragaloside IV also stimulated cell migration, increased tube formation, and promoted angiogenesis in the chick chorioallantoic membrane assay. All angiogenic effects of astragaloside IV were reversed by the PI3K inhibitor. Taken together, our data collectively reveal that astragaloside IV is a novel regulator of HIF-1␣ and angiogenesis through the PI3K/Akt pathway in HUVECs that are exposed to hypoxia.

Astragaloside IV Ameliorates Renal Fibrosis via the Inhibition of Mitogen-Activated Protein Kinases and Antiapoptosis In Vivo and In Vitro

“…These results suggest that increasing the activation of the JNK and p38 MAPK pathways might play a prominent role in renal tubular cell apoptosis (thus, subsequently accelerating the progression of renal tubulointerstitial fibrosis), and the inhibitory effect of AS-IV on cell apoptosis may be related to the inhibition of these two MAPK signaling pathways. Similar studies have been performed on the protective effect of AS-IV in renal injury and pathology (Meng et al, 2011;Zhang et al, 2011;Li et al, 2012;Qin et al, 2012;Gui et al, 2013;Qi et al, 2014). Meng et al (2011) performed a study in UUO rats using AS-IV and ferulic acid as treatments.…”

Astragaloside IV Improves Vasodilatation Function by Regulating the PI3K/Akt/eNOS Signaling Pathway in Rat Aorta Endothelial Cells

“…Akt is activated in response to PI3K and its lipid products phosphatidylinositol 3, 4, 5-trisphosphate (Ptdlns [3,4,5]P3, PIP 3 ) and Ptdlns(3,4) P 2 (PIP 2 ) [40]. Activated PI3K/Akt signaling induces further eNOS activation which is localized on the cellular membranes and leads to the production of NO [41]. eNOS is the NOS isoform that is expressed abundantly in the cardiovascular tissues, especially in the endothelium.…”

“…The activation of the PI3K/Akt pathway caused by AGIV is a pivotal event in suppressing cardiomyocyte apoptosis [53]. AGIV Color version available online treatment significantly stimulates angiogenesis via the PI3K/Akt signaling pathway [41]. As a Ca 2+ antagonist, AGIV blocks the superior receptor-operated Ca 2+ and relaxes the vessels by regulating NO from vascular endothelial cells and vascular smooth-muscle cells [54].…”

Astragaloside IV enhances diabetic wound healing involving upregulation of alternatively activated macrophages

“…It may induce a keratinocyte proliferation and migration, which is an essential feature of reepithelialization [12]. It also promotes vascular cell migration and proliferation, which is an important component of new vessel formation and vascular maturation [35]. In the current study, we found that local administration of AS-IV into cutaneous wounds was sufficient to facilitate the rate of wound healing in diabetic mice.…”