CRCardiovascular Reviews3083-48802981-8109Bio-Byword Scientific Publishing Pty. Ltd.10.26689/cr.v2i4.9345ArticleResearch Progress of Astragaloside IV in the Treatment of Cardiovascular Diseaseshttps://artdesignp.com/journal/CR/2/4/10.26689/cr.v2i4.9345ZhangRui,LiuYan,JiaFuyun,YanJingshun,LiShengsong,ZhangWenchao,MaYinan,ZhangZhengwei,XuQiang2025242025-01-13Cardiovascular disease (CVD) continues to dominate as the primary cause of mortality and morbidity worldwide, constituting a pressing global health concern. In contrast to Western medicine, traditional Chinese medicine (TCM) offers a holistic, side-effect-minimizing, and highly efficacious approach to tackling CVD challenges. Among the myriad herbs utilized in TCM, Huangqi (HQ), particularly in the realm of cardiovascular therapeutics, has enjoyed an esteemed status spanning millennia. Astragaloside IV (AS-IV), a saponin derivative meticulously extracted from the roots of the renowned Chinese medicinal plant Astragalus membranaceus, has garnered significant attention for its multifaceted cardioprotective capabilities. These encompass antioxidant stress mitigation, anti-inflammatory actions, anti-apoptotic effects, inhibition of cardiomyocyte hypertrophy, and attenuation of myocardial fibrosis, among others. Consequently, pharmacokinetic and toxicological evaluations underscore AS-IV’s low bioavailability yet commendable safety profile, with a notable caveat of prudence when administering to pregnant individuals. The present article delves into the most recent advancements in understanding the therapeutic impacts and underlying mechanisms of AS-IV in the context of cardiovascular diseases. By consolidating these cutting-edge findings, we aspire to establish a robust theoretical foundation that can propel the development of AS-IV as an innovative therapeutic agent for the treatment of CVDs, thereby contributing to the global endeavor to combat this pervasive health burden.

Lin J, Wang Q, Zhou S, et al., 2022, Tetramethylpyrazine: A Review on Its Mechanisms and Functions. Biomed Pharmacother, 150: 113005.

Yang Y, Hong M, Lian WW, et al., 2022, Review of the Pharmacological Effects of Astragaloside IV and Its Autophagic Mechanism in Association with Inflammation. World Journal of Clinical Cases, 10: 10004–10016.

Huang X, Tang L, Wang F, et al., 2014, Astragaloside IV Attenuates Allergic Inflammation by Regulation Th1/Th2 Cytokine and Enhancement CD4(+)CD25(+)Foxp3 T Cells in Ovalbumin-Induced Asthma. Immunobiology, 219: 565–571.

Li L, Zou J, Zhou M, et al., 2024, Phenylsulfate-Induced Oxidative Stress and Mitochondrial Dysfunction in Podocytes Are Ameliorated by Astragaloside IV Activation of the SIRT1/PGC1α /Nrf1 Signaling Pathway. Biomedical Pharmacotheraphy, 177: 117008.

Wan J, Zhang Z, Wu C, et al., 2023, Astragaloside IV Derivative HHQ16 Ameliorates Infarction-Induced Hypertrophy and Heart Failure Through Degradation of lncRNA4012/9456. Signal Transduction and Targeted Therapy, 8: 414.

Zhang J, Huang J, Lan J, et al., 2024, Astragaloside IV Protects Against Autoimmune Myasthenia Gravis in Rats via Regulation of Mitophagy and Apoptosis. Molecular Medicine Reports, 30(1): 129.

Shi L, Deng J, He J, et al., 2024, Integrative Transcriptomics and Proteomics Analysis Reveal the Protection of Astragaloside IV Against Myocardial Fibrosis by Regulating Senescence. European Journal of Pharmacology, 975: 176632.

Moens AL, Claeys MJ, Timmermans JP, et al., 2005, Myocardial Ischemia/Reperfusion-Injury, a Clinical View on a Complex Pathophysiological Process. International Journal of Cardiology, 100: 179–190.

Chouchani ET, Pell VR, Gaude E, et al., 2014, Ischaemic Accumulation of Succinate Controls Reperfusion Injury Through Mitochondrial ROS. Nature, 515: 431–435.

Jiang M, Ni J, Cao Y, et al., 2019, Astragaloside IV Attenuates Myocardial Ischemia-Reperfusion Injury from Oxidative Stress by Regulating Succinate, Lysophospholipid Metabolism, and ROS Scavenging System. Oxidative Medicine and Cellular Longevity, 2019: 9137654.

Frame S, Cohen P, 2001, GSK3 Takes Centre Stage More Than 20 Years After Its Discovery. The Biochemical Journal, 359: 1–16.

He Y, Xi J, Zheng H, et al., 2012, Astragaloside IV Inhibits Oxidative Stress-Induced Mitochondrial Permeability Transition Pore Opening by Inactivating GSK-3β via Nitric Oxide in H9c2 Cardiac Cells. Oxidative Medicine and Cellular Longevity, 2012: 935738.

Wei D, Xu H, Gai X, et al., 2019, Astragaloside IV Alleviates Myocardial Ischemia-Reperfusion Injury in Rats Through Regulating PI3K/AKT/GSK-3β Signaling Pathways. Acta Cirúrgica Brasileira, 34: e201900708.

McLaughlin D, Zhao Y, O’Neill KM, et al., 2017, Signalling Mechanisms Underlying Doxorubicin and Nox2 NADPH Oxidase-Induced Cardiomyopathy: Involvement of Mitofusin-2. British Journal of Pharmacology, 174: 3677–3695.

Lin J, Fang L, Li H, et al., 2019, Astragaloside IV Alleviates Doxorubicin Induced Cardiomyopathy by Inhibiting NADPH Oxidase Derived Oxidative Stress. European Journal of Pharmacology, 859: 172490.

Zhuang Z, Wang ZH, Deng LH, et al., 2019, Astragaloside IV Exerts Cardioprotection in Animal Models of Viral Myocarditis: A Preclinical Systematic Review and Meta-Analysis. Frontiers in Pharmacology, 10: 1388.

Miyazaki T, Miyazaki A, 2018, Dysregulation of Calpain Proteolytic Systems Underlies Degenerative Vascular Disorders. Journal of Atherosclerosis and Thrombosis, 25: 1–15.

Nie Q, Zhu L, Zhang L, et al., 2019, Astragaloside IV Protects Against Hyperglycemia-Induced Vascular Endothelial Dysfunction by Inhibiting Oxidative Stress and Calpain-1 Activation. Life Sci, 232: 116662.

Oever IA, Raterman HG, Nurmohamed MT, et al., 2010, Endothelial Dysfunction, Inflammation, and Apoptosis in Diabetes Mellitus. Mediators of Inflammation, 2010: 792393.

Nitenberg A, Antony I, 1998, Coronary Vascular Endothelium, a Common Target in Patients with Diabetes Mellitus, Cigarette Smoking, Hypercholesterolaemia, Hypertension, and Menopausal Status. Nephrology, Dialysis, Transplantation, 13(Suppl 4): 16–19.

Sans M, Panés J, Ardite E, et al., 1999, VCAM-1 and ICAM-1 Mediate Leukocyte-Endothelial Cell Adhesion in Rat Experimental Colitis. Gastroenterology, 116: 874–883.

Bhaskar S, Sudhakaran PR, Helen A, 2016, Quercetin Attenuates Atherosclerotic Inflammation and Adhesion Molecule Expression by Modulating TLR-NF-κB Signaling Pathway. Cellular Immunology, 310: 131–140.

Leng B, Tang F, Lu M, et al., 2018, Astragaloside IV Improves Vascular Endothelial Dysfunction by Inhibiting the TLR4/NF-κB Signaling Pathway. Life Sciences, 209: 111–121.

Pietro N, Formoso G, Pandolfi A, 2016, Physiology and Pathophysiology of OxLDL Uptake by Vascular Wall Cells in Atherosclerosis. Vascular Pharmacology, 84: 1–7.

Jiang Y, Wang M, Huang K, et al., 2012, Oxidized Low-Density Lipoprotein Induces Secretion of Interleukin-1β by Macrophages via Reactive Oxygen Species-Dependent NLRP3 Inflammasome Activation. Biochemical and Biophysical Research Communications, 425: 121–126.

Qian W, Cai X, Qian Q, et al., 2019, Astragaloside IV Protects Endothelial Progenitor Cells from the Damage of Ox-LDL via the LOX-1/NLRP3 Inflammasome Pathway. Drug Design, Development and Therapy, 13: 2579–2589.

Zhang X, Li M, Wang H, 2019, Astragaloside IV Alleviates the Myocardial Damage Induced by Lipopolysaccharide via the Toll-Like Receptor 4 (TLR4)/Nuclear Factor Kappa B (NF-κB)/Proliferator-Activated Receptor α (PPARα) Signaling Pathway. Medical Science Monitor, 25: 7158–7168.

Yang J, Wang HX, Zhang YJ, et al., 2013, Astragaloside IV Attenuates Inflammatory Cytokines by Inhibiting TLR4/NF-κB Signaling Pathway in Isoproterenol-Induced Myocardial Hypertrophy. Journal of Ethnopharmacology, 150: 1062–1070.

Shi H, Zhou P, Gao G, et al., 2021, Astragaloside IV Prevents Acute Myocardial Infarction by Inhibiting the TLR4/MyD88/NF-κB Signaling Pathway. Journal of Food Biochemistry, 45: e13757.

Huang X, Zhang MZ, Liu B, et al., 2021, Astragaloside IV Attenuates Polymicrobial Sepsis-Induced Cardiac Dysfunction in Rats via IKK/NF-κB Pathway. Chinese Journal of Integrative Medicine, 27: 825–831.

Prabhu S, Wang G, Luo J, et al., 2003, Beta-Adrenergic Receptor Blockade Modulates Bcl-X(S) Expression and Reduces Apoptosis in Failing Myocardium. Journal of Molecular and Cellular Cardiology, 35: 483–493.

Schroer J, Warm D, Rosa F, et al., 2023, Activity-Dependent Regulation of the BAX/BCL-2 Pathway Protects Cortical Neurons from Apoptotic Death During Early Development. Cellular and Molecular Life Sciences, 80: 175.

Bao M, Bade R, Liu H, et al., 2023, Astragaloside IV Against Alzheimer’s Disease via Microglia-Mediated Neuroinflammation Using Network Pharmacology and Experimental Validation. European Journal of Pharmacology, 957: 175992.

Liu T, Yang F, Liu J, et al., 2019, Astragaloside IV Reduces Cardiomyocyte Apoptosis in a Murine Model of Coxsackievirus B3-Induced Viral Myocarditis. Experimental Animals, 68: 549–558.

Mackay K, Mochly-Rosen D, 1999, An Inhibitor of p38 Mitogen-Activated Protein Kinase Protects Neonatal Cardiac Myocytes from Ischemia. Journal of Biological Chemistry, 274: 6272–6279.

Mizukami Y, Okamura T, Miura T, et al., 2001, Phosphorylation of Proteins and Apoptosis Induced by c-Jun N-Terminal Kinase1 Activation in Rat Cardiomyocytes by H(2)O(2) Stimulation. Biochimica et Biophysica Acta, 1540: 213–220.

Sun C, Zeng G, Wang T, et al., 2021, Astragaloside IV Ameliorates Myocardial Infarction Induced Apoptosis and Restores Cardiac Function. Frontiers in Cell and Developmental Biology, 9: 671255.

Suryakumar G, Kasiganesan H, Balasubramanian S, et al., 2010, Lack of Beta3 Integrin Signaling Contributes to Calpain-Mediated Myocardial Cell Loss in Pressure-Overloaded Myocardium. Journal of Cardiovascular Pharmacology, 55: 567–573.

Chen Q, Paillard M, Gomez L, et al., 2011, Activation of Mitochondrial μ-Calpain Increases AIF Cleavage in Cardiac Mitochondria During Ischemia-Reperfusion. Biochemical and Biophysical Research Communications, 415: 533–538.

Mei M, Tang F, Lu M, et al., 2015, Astragaloside IV Attenuates Apoptosis of Hypertrophic Cardiomyocyte Through Inhibiting Oxidative Stress and Calpain-1 Activation. Environmental Toxicology and Pharmacology, 40: 764–773.

Yang JJ, Zhang XH, Ma XH, et al., 2020, Astragaloside IV Enhances GATA-4 Mediated Myocardial Protection Effect in Hypoxia/Reoxygenation Injured H9c2 Cells. Nutrition, Metabolism, and Cardiovascular Diseases, 30: 829–842.

Semenza GL, 2012, Hypoxia-Inducible Factors in Physiology and Medicine. Cell, 148: 399–408.

Si J, Wang N, Wang H, et al., 2014, HIF-1α Signaling Activation by Post-Ischemia Treatment with Astragaloside IV Attenuates Myocardial Ischemia-Reperfusion Injury. PLoS One, 9: e107832.

Iwasaki H, Kawamoto A, Tjwa M, et al., 2011, PlGF Repairs Myocardial Ischemia Through Mechanisms of Angiogenesis, Cardioprotection, and Recruitment of Myo-Angiogenic Competent Marrow Progenitors. PLoS One, 6: e24872.

Yu JM, Zhang XB, Jiang W, et al., 2015, Astragalosides Promote Angiogenesis via Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor in a Rat Model of Myocardial Infarction. Molecular Medicine Reports, 12: 6718–6726.

Wang S, Chen J, Fu Y, et al., 2015, Promotion of Astragaloside IV for EA-hy926 Cell Proliferation and Angiogenic Activity via ERK1/2 Pathway. Journal of Nanoscience and Nanotechnology, 15: 4239–4244.

Wang SG, Xu Y, Chen JD, et al., 2013, Astragaloside IV Stimulates Angiogenesis and Increases Nitric Oxide Accumulation via JAK2/STAT3 and ERK1/2 Pathway. Molecules (Basel, Switzerland), 18: 12809–12819.

Zhang Y, Hu G, Li S, et al., 2012, Pro-Angiogenic Activity of Astragaloside IV in HUVECs In Vitro and Zebrafish In Vivo. Molecular Medicine Reports, 5: 805–811.

Feng Q, Li X, Qin X, et al., 2020, PTEN Inhibitor Improves Vascular Remodeling and Cardiac Function After Myocardial Infarction Through PI3k/Akt/VEGF Signaling Pathway. Molecular Medicine (Cambridge, Mass.), 26: 111.

Cheng S, Zhang X, Feng Q, et al., 2019, Astragaloside IV Exerts Angiogenesis and Cardioprotection After Myocardial Infarction via Regulating PTEN/PI3K/Akt Signaling Pathway. Life Science, 227: 82–93.

Hilfiker-Kleiner D, Hilfiker A, Fuchs M, et al., 2004, Signal Transducer and Activator of Transcription 3 is Required for Myocardial Capillary Growth, Control of Interstitial Matrix Deposition, and Heart Protection from Ischemic Injury. Circulation Research, 95: 187–195.

Sui YB, Wang Y, Liu L, et al., 2019, Astragaloside IV Alleviates Heart Failure by Promoting Angiogenesis Through the JAK-STAT3 Pathway. Pharmaceutical Biology, 57: 48–54.

Simon AM, McWhorter AR, 2003, Decreased Intercellular Dye-Transfer and Downregulation of Non-Ablated Connexins in Aortic Endothelium Deficient in Connexin37 or Connexin40. Journal of Cell Science, 116: 2223–2236.

Alonso F, Domingos-Pereira S, Le Gal L, et al., 2016, Targeting Endothelial Connexin40 Inhibits Tumor Growth by Reducing Angiogenesis and Improving Vessel Perfusion. Oncotarget, 7: 14015–14028.

Leybaert L, Lampe PD, Dhein S, et al., 2017, Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications. Pharmacological Reviews, 69: 396–478.

Li Z, Zhang S, Cao L, et al., 2018, Tanshinone IIA and Astragaloside IV Promote the Angiogenesis of Mesenchymal Stem Cell-Derived Endothelial Cell-Like Cells via Upregulation of Cx37, Cx40, and Cx43. Experimental and Therapeutic Medicine, 15: 1847–1854.

Wang C, Li Y, Yang X, et al., 2017, Tetramethylpyrazine and Astragaloside IV Synergistically Ameliorate Left Ventricular Remodeling and Preserve Cardiac Function in a Rat Myocardial Infarction Model. Journal of Cardiovascular Pharmacology, 69: 34–40.

Gaasch WH, Delorey DE, Sutton MGJ, et al., 2008, Patterns of Structural and Functional Remodeling of the Left Ventricle in Chronic Heart Failure. The American Journal of Cardiology, 102: 459–462.

Kang YJ, 2006, Cardiac Hypertrophy: A Risk Factor for QT-Prolongation and Cardiac Sudden Death. Toxicologic Pathology, 34: 58–66.

Shi H, Ma C, Liu Y, et al., 2009, Inhibitory Effect on Activated Renin-Angiotensin System by Astragaloside IV in Rats with Pressure-Overload Induced Cardiac Hypertrophy. China Journal of Chinese Materia Medica, 34: 3242–3246.

Shostak K, Chariot A, 2015, EGFR and NF-κB: Partners in Cancer. Trends in Molecular Medicine, 21: 385–393.

Liu M, Wang H, Wang J, et al., 2014, Astragaloside IV Protects Against Cardiac Hypertrophy via Inhibiting the Ca2+/CaN Signaling Pathway. Planta Medica, 80: 63–69.

Zhang ZC, Li SJ, Yang YZ, 2007, Effect of Astragaloside on Myocardial Fibrosis in Chronic Myocarditis. Chinese Journal of Integrated Traditional and Western Medicine, 27: 728–731.

Zhang S, Tang F, Yang Y, et al., 2015, Astragaloside IV Protects Against Isoproterenol-Induced Cardiac Hypertrophy by Regulating NF-κB/PGC-1α Signaling Mediated Energy Biosynthesis. PLoS One, 10: e0118759.

Kania G, Blyszczuk P, Eriksson U, 2009, Mechanisms of Cardiac Fibrosis in Inflammatory Heart Disease. Trends in Cardiovascular Medicine, 19: 247–252.

Xu XL, Ji H, Gu SY, et al., 2007, Modification of Alterations in Cardiac Function and Sarcoplasmic Reticulum by Astragaloside IV in Myocardial Injury in Vivo. European Journal of Pharmacology, 568: 203–212.

Dai H, Jia G, Lu M, et al., 2017, Astragaloside IV Inhibits Isoprenaline-Induced Cardiac Fibrosis by Targeting the Reactive Oxygen Species/Mitogen-Activated Protein Kinase Signaling Axis. Molecular Medicine Reports, 15: 1765–1770.

Hu HH, Chen DQ, Wang YN, et al., 2018, New Insights into TGF-β/Smad Signaling in Tissue Fibrosis. Chemico-Biological Interactions, 292: 76–83.

Abderrazak A, Syrovets T, Couchie D, et al., 2015, NLRP3 Inflammasome: From a Danger Signal Sensor to a Regulatory Node of Oxidative Stress and Inflammatory Diseases. Redox Biology, 4: 296–307.

Wan Y, Xu L, Wang Y, et al., 2018, Preventive Effects of Astragaloside IV and Its Active Sapogenin Cycloastragenol on Cardiac Fibrosis of Mice by Inhibiting the NLRP3 Inflammasome. European Journal of Pharmacology, 833: 545–554.

Zhang X, Qu H, Yang T, et al., 2022, Astragaloside IV Attenuates MI-Induced Myocardial Fibrosis and Cardiac Remodeling by Inhibiting ROS/Caspase-1/GSDMD Signaling Pathway. Cell Cycle (Georgetown, Tex.), 21: 2309–2322.

Zhou JY, Fan Y, Kong JL, et al., 2000, Effects of Components Isolated from Astragalus Membranaceus Bunge on Cardiac Function Injured by Myocardial Ischemia Reperfusion in Rats. China Journal of Chinese Materia Medica, 25: 300–302.

Wenjuan L, Jing Z, Hongyue M, et al., 2012, Effects of Astragaloside IV, Total Ginseng Saponins, and Total American Ginseng Saponins on Arrhythmia in Mice Induced by Bufotonin. China Journal of Traditional Chinese Medicine and Pharmacy, 28: 61–64.

Jun B, Leilei B, Zhiyong C, et al., 2005, The Effect of Astragaloside IV on the Hemorheology of Rabbits. Pharmaceutical Journal of Chinese People’s Liberation Army, 456–458.

Zhang WD, Zhang C, Liu RH, et al., 2006, Preclinical Pharmacokinetics and Tissue Distribution of a Natural Cardioprotective Agent Astragaloside IV in Rats and Dogs. Life Sciences, 79: 808–815.

Gu Y, Wang G, Pan G, et al., 2004, Transport and Bioavailability Studies of Astragaloside IV, an Active Ingredient in Radix Astragali. Basic & Clinical Pharmacology & Toxicology, 95: 295–298.

Du Y, Zhang Q, Chen GG, et al., 2005, Pharmacokinetics of Astragaloside IV in Rats by Liquid Chromatography Coupled with Tandem Mass Spectrometry. European Journal of Drug Metabolism and Pharmacokinetics, 30: 269–273.

Huang CR, Wang GJ, Wu XL, et al., 2006, Absorption Enhancement Study of Astragaloside IV Based on Its Transport Mechanism in Caco-2 Cells. European Journal of Drug Metabolism and Pharmacokinetics, 31: 5–10.

Zhang Q, Zhu LL, Chen GG, et al., 2007, Pharmacokinetics of Astragaloside IV in Beagle Dogs. European Journal of Drug Metabolism and Pharmacokinetics, 32: 75–79.

Huang HP, Liu CX, Li YL, et al., 2008, Study on Absorption Kinetics of Astragaloside IV in Rats’ Intestines. China Journal of Chinese Materia Medica, 33: 1609–1611.

Jian L, Chunlai L, Liqin R, et al., 2010, Bioavailability of Astragaloside IV Hydroxypropyl-β-Cyclodextrin Inclusion Complex in Rats. ChinaPharm, 13: 469–471.

Yu SY, Ouyang HT, Yang JY, et al., 2007, Subchronic Toxicity Studies of Radix Astragali Extract in Rats and Dogs. Journal of Ethnopharmacology, 110: 352–355.

Jiangbo Z, Xuying W, Yuping Z, et al., 2009, Effect of Astragaloside IV on the Embryo-Fetal Development of Sprague-Dawley Rats and New Zealand White Rabbits. Journal of Applied Toxicology, 29: 381–385.

Xuying W, Jiangbo Z, Yuping Z, et al., 2010, Effect of Astragaloside IV on the General and Peripartum Reproductive Toxicity in Sprague-Dawley Rats. International Journal of Toxicology, 29: 505–516.

Liu ZH, Liu HB, Wang J, 2018, Astragaloside IV Protects Against the Pathological Cardiac Hypertrophy in Mice. Biomedicine & Pharmacotherapy, 97: 1468–1478.

Nie P, Meng F, Zhang J, et al., 2019, Astragaloside IV Exerts a Myocardial Protective Effect Against Cardiac Hypertrophy in Rats, Partially via Activating the Nrf2/HO-1 Signaling Pathway. Oxidative Medicine and Cellular Longevity, 2019: 4625912.

Zhang W, Wang X, Li J, et al., 2021, Astragaloside IV Reduces OxLDL-Induced BNP Overexpression by Regulating HDAC. Journal of Healthcare Engineering, 2021: 3433615.

Shan ZX, Lin QX, Fu YH, et al., 2009, Upregulated Expression of miR-1/miR-206 in a Rat Model of Myocardial Infarction. Biochemical and Biophysical Research Communications, 381: 597–601.

Wang Q, Chen W, Yang X, et al., 2022, Inhibition of miRNA-1-Mediated Inflammation and Autophagy by Astragaloside IV Improves Lipopolysaccharide-Induced Cardiac Dysfunction in Rats. Journal of Inflammation Research, 15: 2617–2629.