Astragaloside IV: An Effective Drug for the Treatment of Cardiovascular Diseases

Figures & data

Table 1 ¹H and ¹³C NMR Spectroscopic Data of AS-IV

No. C	δC	δH
1	32.4
2	30.4
3	88.7	5.33 dd (12, 4.5)
4	42.8
5	52.7	1.92 d (8.5)
6	79.4	3.80 ddd (8.5, 8.5, 4)
7	34.8
8	45.9
9	21.2
10	29.2
11	26.3
12	33.5
13	45.2
14	46.4
15	46.4
16	73.5	5.03 m
17	58.4	2.53 d (9)
18	21.3	3H,1.42 s
19	29.0	0.21 d (4); 0.60 d (4)
20	87.4
21	27.2	3H,1.30 s
22	35.0	1.67 m; 3.14 dd (20, 10.5)
23	26.6
24	81.8	3.88 m
25	71.4
26	28.3	3H,1.59 s
27	28.7	3H,1.30 s
28	28.8	3H,2.06 s
29	16.8	3H,1.38 s
30	20.0	3H,0.94 s
1’	107.8	4.87 d (7.5)
2’	75.7
3’	78.3
4’	72.0
5’	67.2
1ʹ’	105.4	4.92 d (7.5)
2ʹ’	75.7
3ʹ’	79.3
4ʹ’	71.4
5ʹ’	78.7
6ʹ’	63.3

Table 2 Pharmacokinetic Parameters of AS-IV (8 mg·kg⁻¹) Injected into the Tail Vein of Rats

Parameters	Unit	Value
K12	min^−1	0.00024
K21	min^−1	0.002
K10	min^−1	0.0066
T1/2α (Distribution half-life)	min	110.5
T1/2β (Elimination half-life)	min	331.6
Vc (Apparent volume of distribution of central compartment)	mL·kg^−1	0.00032
MRT (Mean residence time)	min	103.9571
Vd (Apparent volume of distribution)	mL·kg^−1	175.142
CL (Clearance)	mL/(min·kg)	0.3661
AUCt (The total area under concentration–time curve)	min/(μg·mL)	11,880.31
AUCi (The incremental area under concentration–time curve)	min/(μg·mL)	13,707.13

Figure 1 The structural formula of AS-IV.

Figure 2 The mechanism of AS-IV protection of cardiomyocytes from hypoxia-ischemia injury. Hypoxic-ischemic injury will lead to the downregulation of Bcl-2 expression, upregulation of Bax expression, opening of mPTP, release of Cyt C, and activation of Caspase-3, leading to apoptosis. The addition of AS-IV can inhibit this series of processes and protect cardiomyocytes.

Table 3 Mechanisms of AS-IV in the Treatment of Cardiac Hypertrophy

Research Subjects	Induction Methods	Mechanism	Refs
Rats and heart H9C2 cells	Isoproterenol or GdCl3	Regulates CaSR-mediated [Ca^2+](i), CaMKII and CaN signaling pathways, reduces heart function and mitochondrial structural damage	[^Citation58]
Sprague-Dawley rats and H9C2 cells	Isoproterenol	Reduces oxidative stress and activates calpain-1, displays anti-apoptotic effects	[^Citation59]
Primary Cardiomyocytes	Lipopolysaccharide	Inhibits cardiac hypertrophy through the Ca^2+-mediated CaN signaling pathway	[^Citation60]
Sprague-Dawley rats and neonatal rat ventricular myocytes	Isoproterenol	Modulates NF-κB/PGC-1α signaling to prevent cardiac hypertrophy	[^Citation61]
Rats and heart H9C2 cells	Abdominal aortic coarctation or angiotensin II	Upregulates Nrf2, stimulates the Nrf2/HO-1 signaling pathway to improve heart structure and function	[^Citation62]
Sprague-Dawley rats and neonatal rat cardiomyocytes	Isoproterenol	Inhibits the TLR4/NF-κB signaling pathway and reduce inflammation	[^Citation63]
Mice, inbred C57BL	Aortic banding surgery	Improves IKKepsilon inhibitory factor, inhibits TBK1/PI3K/AKT activity	[^Citation64]
Primary rat cardiomyocytes	ET-1	Inhibits ET-1 induced cardiomyocyte hypertrophy, affects the expression of signaling molecules in the vitamin D axis	[^Citation65]

Table 4 Mechanisms of AS-IV Action in the Treatment of Myocardial Fibrosis

Research Subjects	Induction Methods	Mechanism	Refs
Mice, inbred C57BL	Coxsackievirus B3	Reduces the expression of FAS, FASL, caspase-8 and caspase-3, inhibits the activation of the FAS/FASL signaling pathway	[^Citation66]
Mice, inbred BALB C	Coxsackievirus B3	Downregulates the TGF-β1-Smad signaling pathway and reduces the level of type I collagen	[^Citation67]
Mice, Inbred BALB C	Coxsackievirus B3	Downregulates the expression of TGF-β1 and upregulates the expression of MMP-13 and MMP-14	[^Citation68]
Mice, Inbred BALB C and primary cardiac fibroblasts	Isoproterenol	Downregulates the mRNA expression of NLRP3, caspase-1, IL-18 and IL-6, inhibits the NLRP3 pathway	[^Citation69]
Sprague-Dawley rats	Isoproterenol	Reduces the expression of TRPM7 and its mRNA, inhibits the activation of the TGF-β/Smads pathway, and inhibits fibrosis through the miR-135a-TRPM7-TGF-β/Smads pathway.	[^Citation71]
Sprague-Dawley rats and primary cardiac fibroblasts	Isoproterenol	Inhibits the increase of ROS content and the upregulation of cardiotrophin 1 expression	[^Citation72]
Sprague-Dawley rats and primary cardiac fibroblasts	Isoproterenol	Inhibits ROS-mediated activation of mitogen-activated protein kinase (MAPK)	[^Citation73]
Sprague-Dawley rats	Isoproterenol	Decreases TGF-β1, Smad 2/3, and Smad 4 protein expression levels, upregulates Smad 7 protein expression level, and regulates the TGF-β1/Smad signaling pathway	[^Citation74]

Table 5 Mechanisms of AS-IV in the Treatment of Endothelial Dysfunction

Research Subjects	Induction Methods	Mechanism	Refs
Sprague-Dawley rats	Isoproterenol	Reduces eNOS-mediated oxidative stress and inhibits the ROS-NF-κB pathway	[^Citation84]
Sprague-Dawley rats and Human umbilical vein endothelial cells	Streptozotocin	Reduces oxidative stress and calpain-1, improves endothelial dysfunction	[^Citation85]
Sprague-Dawley rats and Human umbilical vein endothelial cells	Streptozotocin	Reduces the content of IL-6 and TNF-α, decreases the expression of VCAM-1, ICAM-1, TLR4, and nuclear NF-κB p65, regulates the TLR4/NF- κB signaling pathway	[^Citation86]
Sprague-Dawley rats	Fructose	Improves glucose tolerance and endothelium-dependent vasodilation, increases the levels of NOx and cGMP	[^Citation87]
Human umbilical vein endothelial cells	Homocysteine	Increases ROS activity, ameliorates the inactivation of NOS, and regulates the NO/NOS pathway	[^Citation88]

Table 6 Mechanisms of AS-IV Promotion of Angiogenesis

Research Subjects	Intervention Methods	Mechanism	Refs
Sprague-Dawley rats	Ligation of left coronary artery	Induces phosphorylation of JAK and STAT3 and regulates the JAK-STAT3 pathway	[^Citation89]
Wistar rats	Ligation of left coronary artery	Increases the mRNA and protein expression levels of VEGF and bFGF, increases microvessel density	[^Citation90]
Sprague Dawley rats and Human umbilical vein endothelial cells	Ligation of left coronary artery	Reduces ultrastructural damage and promotes angiogenesis, promotes cell proliferation and tube formation, and induces the activation of the PTEN/PI3K/Akt signaling pathway	[^Citation91]
Sprague-Dawley rats	Ligation of left anterior descending branch	Increases the mRNA and protein expression of PKD1, HDAC5 and VEGF, and regulates the PKD1-HDAC5-VEGF pathway	[^Citation92]
Mesenchymal stem cells isolated from the femurs and tibias of Sprague Dawley rats	VEGF and bFGF promote the differentiation of MSCs into EC-like cells	Enhances the proliferation and tube formation ability of EC-like cells, and upregulates the expression of Cx37, Cx40, and Cx43	[^Citation93]
Primary endothelial cells and smooth muscle cells, Sprague Dawley rats	Place the drug-loaded stent under the back of the rat	Increases cell viability and extracellular matrix secretion of endothelial and smooth muscle cells, increases vascular density and decreases inflammatory response after drug loading	[^Citation94]

LiuZH, LiuHB, WangJ. Astragaloside IV protects against the pathological cardiac hypertrophy in mice. Biomed Pharmacother. 2018;97:1468–1478. doi:10.1016/j.biopha.2017.09.09229793309

 PubMed Web of Science ®Google Scholar

ChenY, ChenJ, GaoJ, ChaiYH, LiW, QinZ. Effect of astragaloside on vitamin D-receptor expression after endothelin-1-induced cardiomyocyte injury. Afr J Tradit Complement Altern Med. 2017;14(4):278–288. doi:10.21010/ajtcam.v14i4.31

 Google Scholar

ZhangS, TangF, YangY, et al. Astragaloside IV protects against isoproterenol-induced cardiac hypertrophy by regulating NF-kappaB/PGC-1alpha signaling mediated energy biosynthesis. PLoS One. 2015;10(3):e0118759. doi:10.1371/journal.pone.011875925738576

 PubMed Web of Science ®Google Scholar

NieP, MengF, ZhangJ, WeiX, ShenC. Astragaloside IV exerts a myocardial protective effect against cardiac hypertrophy in rats, partially via activating the Nrf2/HO-1 signaling pathway. Oxid Med Cell Longev. 2019;2019:4625912. doi:10.1155/2019/462591231285785

 PubMed Web of Science ®Google Scholar

MeiM, TangF, LuM, et al. Astragaloside IV attenuates apoptosis of hypertrophic cardiomyocyte through inhibiting oxidative stress and calpain-1 activation. Environ Toxicol Pharmacol. 2015;40(3):764–773. doi:10.1016/j.etap.2015.09.00726433482

 PubMed Web of Science ®Google Scholar

LuM, WangH, WangJ, et al. Astragaloside IV protects against cardiac hypertrophy via inhibiting the Ca2+/CaN signaling pathway. Planta Med. 2014;80(1):63–69. doi:10.1055/s-0033-136012924338553

 PubMed Web of Science ®Google Scholar

YangJ, WangHX, ZhangYJ, et al. Astragaloside IV attenuates inflammatory cytokines by inhibiting TLR4/NF-κB signaling pathway in isoproterenol-induced myocardial hypertrophy. J Ethnopharmacol. 2013;150(3):1062–1070. doi:10.1016/j.jep.2013.10.01724432369

 PubMed Web of Science ®Google Scholar

LiuT, YangF, LiuJ, et al. Astragaloside IV reduces cardiomyocyte apoptosis in a murine model of coxsackievirus B3-induced viral myocarditis. Exp Anim. 2019;68(4):549–558. doi:10.1538/expanim.19-003731243190

 PubMed Web of Science ®Google Scholar

ChenP, XieY, ShenE, et al. Astragaloside IV attenuates myocardial fibrosis by inhibiting TGF-beta1 signaling in coxsackievirus B3-induced cardiomyopathy. Eur J Pharmacol. 2011;658(23):168–174. doi:10.1016/j.ejphar.2011.02.04021371462

 PubMed Web of Science ®Google Scholar

ZhangZC, LiSJ, YangYZ. Effect of astragaloside on myocardial fibrosis in chronic myocarditis. Chin J Integrat Chin West Med. 2007;27(8):728–731.

 Google Scholar

WanY, XuL, WangY, TuerdiN, YeM, QiR. Preventive effects of Astragaloside IV and its active sapogenin cycloastragenol on cardiac fibrosis of mice by inhibiting the NLRP3 inflammasome. Eur J Pharmacol. 2018;833:545–554. doi:10.1016/j.ejphar.2018.06.01629913124

 PubMed Web of Science ®Google Scholar

LuJ, WangQY, ZhouY, et al. Astragaloside IV against cardiac fibrosis by inhibiting TRPM7 channel. Phytomedicine. 2017;30:10–17. doi:10.1016/j.phymed.2017.04.00228545665

 PubMed Web of Science ®Google Scholar

JiaG, LengB, WangH, DaiH. Inhibition of cardiotrophin1 overexpression is involved in the antifibrotic effect of Astragaloside IV. Mol Med Rep. 2017;16(6):8365–8370. doi:10.3892/mmr.2017.767628990065

 PubMed Web of Science ®Google Scholar

DaiH, JiaG, LuM, LiangC, WangY, WangH. Astragaloside IV inhibits isoprenaline-induced cardiac fibrosis by targeting the reactive oxygen species/mitogen-activated protein kinase signaling axis. Mol Med Rep. 2017;15(4):1765–1770. doi:10.3892/mmr.2017.622028260010

 PubMed Web of Science ®Google Scholar

LiJS, ZhuXY, LuML, GaoJH, WangHX, YuXC. Effect of combined intervention of electroacupuncture and Astragaloside IV on myocardial hypertrophy and TGF-beta 1/Smad signaling in rats with myocardial fibrosis. Acupunct Res. 2017;42(6):477–481. doi:10.13702/j.1000-0607.2017.06.002

 Google Scholar

ZhaoM, SunX, LianW, et al. Effects of Astragaloside IV on L-type calcium current and intracellular calcium concentration in cardiac myocytes. Chin Pharm Bull. 2013;29(10):1373–1377. doi:10.3969/j.issn.1001-1978.2013.10.011

 Google Scholar

NieQ, ZhuL, ZhangL, LengB, WangH. Astragaloside IV protects against hyperglycemia-induced vascular endothelial dysfunction by inhibiting oxidative stress and Calpain-1 activation. Life Sci. 2019;232:116662. doi:10.1016/j.lfs.2019.11666231323271

 PubMed Web of Science ®Google Scholar

LengB, TangF, LuM, ZhangZ, WangH, ZhangY. Astragaloside IV improves vascular endothelial dysfunction by inhibiting the TLR4/NF-κB signaling pathway. Life Sci. 2018;209:111–121. doi:10.1016/j.lfs.2018.07.05330081006

 PubMed Web of Science ®Google Scholar

ZhangN, WangXH, MaoSL, ZhaoF. Astragaloside IV improves metabolic syndrome and endothelium dysfunction in fructose-fed rats. Molecules. 2011;16(5):3896–3907. doi:10.3390/molecules1605389621555978

 PubMed Web of Science ®Google Scholar

QiuLH, XieXJ, ZhangBQ. Astragaloside IV improves homocysteine-induced acute phase endothelial dysfunction via antioxidation. Biol Pharm Bull. 2010;33(4):641–646. doi:10.1248/bpb.33.64120410599

 PubMed Web of Science ®Google Scholar

SuiYB, WangY, LiuL, LiuF, ZhangYQ. Astragaloside IV alleviates heart failure by promoting angiogenesis through the JAK-STAT3 pathway. Pharm Biol. 2019;57(1):48–54. doi:10.1080/13880209.2019.156969730905241

 PubMed Web of Science ®Google Scholar

YuJM, ZhangXB, JiangW, WangHD, ZhangYN. Astragalosides promote angiogenesis via vascular endothelial growth factor and basic fibroblast growth factor in a rat model of myocardial infarction. Mol Med Rep. 2015;12(5):6718–6726. doi:10.3892/mmr.2015.430726352430

 PubMed Web of Science ®Google Scholar

ChengS, ZhangX, FengQ, et al. Astragaloside IV exerts angiogenesis and cardioprotection after myocardial infarction via regulating PTEN/PI3K/Akt signaling pathway. Life Sci. 2019;227:82–93. doi:10.1016/j.lfs.2019.04.04031004658

 PubMed Web of Science ®Google Scholar

YangL, LiuN, ZhaoW, et al. Angiogenic function of Astragaloside IV in rats with myocardial infarction occurs via the PKD1-HDAC5-VEGF pathway. Exp Ther Med. 2019;17(4):2511–2518. doi:10.3892/etm.2019.727330906439

 PubMed Web of Science ®Google Scholar

LiZ, ZhangS, CaoL, et al. Tanshinone IIA and Astragaloside IV promote the angiogenesis of mesenchymal stem cell-derived endothelial cell-like cells via upregulation of Cx37, Cx40 and Cx43. Exp Ther Med. 2018;15(2):1847–1854. doi:10.3892/etm.2017.563629434774

 PubMed Web of Science ®Google Scholar

WangH, ZhangY, XiaT, et al. Synergistic promotion of blood vessel regeneration by Astragaloside IV and ferulic acid from electrospun fibrous mats. Mol Pharm. 2013;10(6):2394–2403. doi:10.1021/mp400031y23651405

 PubMed Web of Science ®Google Scholar

YuY, LiZ, GuoR, et al. Ononin, sec-O-β-d-glucosylhamaudol and Astragaloside I: antiviral lead compounds identified via high throughput screening and biological validation from traditional Chinese medicine Zhongjing formulary. Pharmacol Res. 2019;145:104248. doi:10.1016/j.phrs.2019.04.03231082475

 PubMed Web of Science ®Google Scholar