Therapeutic Effects of Astragaloside IV on Myocardial Injuries: Multi-Target Identification and Network Analysis

Astragaloside IV (AGS-IV) is a main active ingredient of Astragalus membranaceus Bunge, a medicinal herb used for cardiovascular diseases (CVD). In this work, we investigated the therapeutic mechanisms of AGS-IV at a network level by computer-assisted target identification with the in silico inverse docking program (INVDOCK). Targets included in the analysis covered all signaling pathways thought to be implicated in the therapeutic actions of all CVD drugs approved by US FDA. A total of 39 putative targets were identified. Three of these targets, calcineurin (CN), angiotensin-converting enzyme (ACE), and c-Jun N-terminal kinase (JNK), were experimentally validated at a molecular level. Protective effects of AGS-IV were also compared with the CN inhibitor cyclosporin A (CsA) in cultured cardiomyocytes exposed to adriamycin. Network analysis of protein-protein interactions (PPI) was carried out with reference to the therapeutic profiles of approved CVD drugs. The results suggested that the therapeutic effects of AGS-IV are based upon a combination of blocking calcium influx, vasodilation, anti-thrombosis, anti-oxidation, anti-inflammation and immune regulation.

[1]  A. Barabasi,et al.  Drug—target network , 2007, Nature Biotechnology.

[2]  Chuan Zhang,et al.  Astragaloside IV from Astragalus membranaceus shows cardioprotection during myocardial ischemia in vivo and in vitro. , 2006, Planta medica.

[3]  I. Harary,et al.  In vitro Studies of Single Isolated Beating Heart Cells , 1960, Science.

[4]  Albert,et al.  Emergence of scaling in random networks , 1999, Science.

[5]  R. Ferrari,et al.  Angiotensin-converting enzyme (ACE) inhibitors have different selectivity for bradykinin binding sites of human somatic ACE. , 2007, European journal of pharmacology.

[6]  V. Dzau,et al.  Molecular genetics and genomics of heart failure , 2004, Nature Reviews Genetics.

[7]  R. Virmani,et al.  Apoptosis in myocytes in end-stage heart failure. , 1996, The New England journal of medicine.

[8]  M. Orešič,et al.  Pathways to the analysis of microarray data. , 2005, Trends in biotechnology.

[9]  S. Pongor,et al.  Multiple weak hits confuse complex systems: a transcriptional regulatory network as an example. , 2004, Physical review. E, Statistical, nonlinear, and soft matter physics.

[10]  S. Harrison,et al.  Crystal structure of human calcineurin complexed with cyclosporin A and human cyclophilin , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  H. R. Evans,et al.  Structural details on the binding of antihypertensive drugs captopril and enalaprilat to human testicular angiotensin I-converting enzyme. , 2004, Biochemistry.

[12]  D. Das,et al.  Moderation of myocardial ischemia reperfusion injury by calcium channel and calmodulin receptor inhibition , 2005, Heart and Vessels.

[13]  R. Ravi,et al.  A nearly best-possible approximation algorithm for node-weighted Steiner trees , 1993, IPCO.

[14]  Mark A Sussman,et al.  Prevention of cardiac hypertrophy in mice by calcineurin inhibition. , 1998, Science.

[15]  Jing Zhao,et al.  Insights into the pathogenesis of axial spondyloarthropathy from network and pathway analysis , 2012, BMC Systems Biology.

[16]  Young-Jae Nam,et al.  The Mitochondrial Death Pathway and Cardiac Myocyte Apoptosis , 2004, Circulation research.

[17]  Sandhya Rani,et al.  Human Protein Reference Database—2009 update , 2008, Nucleic Acids Res..

[18]  David S. Wishart,et al.  DrugBank: a comprehensive resource for in silico drug discovery and exploration , 2005, Nucleic Acids Res..

[19]  Weiren Xu,et al.  Effects of Astragaloside IV on heart failure in rats , 2009, Chinese medicine.

[20]  Z. Hong,et al.  Astragaloside IV protects against ischemic brain injury in a murine model of transient focal ischemia , 2004, Neuroscience Letters.

[21]  C. R. Dhanya,et al.  VEGF Signaling: A Therapeutic Target for Cardiovascular Disease , 2008 .

[22]  中尾 光輝,et al.  KEGG(Kyoto Encyclopedia of Genes and Genomes)〔和文〕 (特集 ゲノム医学の現在と未来--基礎と臨床) -- (データベース) , 2000 .

[23]  P. Halloran,et al.  Tissue Distribution of Calcineurin and its Sensitivity to Inhibition by Cyclosporine , 2001, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[24]  P. Gao,et al.  Astragaloside IV dilates aortic vessels from normal and spontaneously hypertensive rats through endothelium-dependent and endothelium-independent ways. , 2006, Planta medica.

[25]  Y.Z. Chen,et al.  Ligand–protein inverse docking and its potential use in the computer search of protein targets of a small molecule , 2001, Proteins.

[26]  D. Mollé,et al.  Inhibitory effect of αS1- and αS2-casein hydrolysates on angiotensin I-converting enzyme in human endothelial cells in vitro, rat aortic tissue ex vivo, and renovascular hypertensive rats in vivo. , 2010, Journal of dairy science.

[27]  C. Wheeler-Jones,et al.  Cell signalling in the cardiovascular system: an overview , 2005, Heart.

[28]  R. Ramasamy,et al.  JAK-STAT pathway in cardiac ischemic stress. , 2005, Vascular pharmacology.

[29]  Hong Jiang,et al.  Valsartan preconditioning protects against myocardial ischemia–reperfusion injury through TLR4/NF-κB signaling pathway , 2009, Molecular and Cellular Biochemistry.

[30]  Qiong Zhang,et al.  ASTRAGALOSIDE IV ATTENUATES HYPOXIA‐INDUCED CARDIOMYOCYTE DAMAGE IN RATS BY UPREGULATING SUPEROXIDE DISMUTASE‐1 LEVELS , 2009, Clinical and experimental pharmacology & physiology.

[31]  P. Hufnagl,et al.  Antiinflammatory activity of astragaloside IV is mediated by inhibition of NF-κB activation and adhesion molecule expression , 2003, Thrombosis and Haemostasis.

[32]  Jing Zhao,et al.  Modular co-evolution of metabolic networks , 2007, BMC Bioinformatics.

[33]  Bing-Hua Jiang,et al.  Cross-talk between Epidermal Growth Factor Receptor and Hypoxia-inducible Factor-1α Signal Pathways Increases Resistance to Apoptosis by Up-regulating Survivin Gene Expression* , 2006, Journal of Biological Chemistry.

[34]  R. Guimerà,et al.  Modularity from fluctuations in random graphs and complex networks. , 2004, Physical review. E, Statistical, nonlinear, and soft matter physics.

[35]  Petter Holme,et al.  Ranking Candidate Disease Genes from Gene Expression and Protein Interaction: A Katz-Centrality Based Approach , 2011, PloS one.

[36]  D. Golenbock,et al.  Proinflammatory phenotype of vascular smooth muscle cells: role of efficient Toll-like receptor 4 signaling. , 2005, American journal of physiology. Heart and circulatory physiology.

[37]  J. Bauer,et al.  Oxidative pathways in cardiovascular disease: roles, mechanisms, and therapeutic implications. , 2001, Pharmacology & therapeutics.

[38]  M E J Newman,et al.  Finding and evaluating community structure in networks. , 2003, Physical review. E, Statistical, nonlinear, and soft matter physics.

[39]  Joy Joseph,et al.  Doxorubicin-induced apoptosis: Implications in cardiotoxicity , 2002, Molecular and Cellular Biochemistry.

[40]  A. Hopkins.  Network pharmacology: the next paradigm in drug discovery. , 2008, Nature chemical biology.

[41]  Xiaohua Ma,et al.  Mechanisms of drug combinations: interaction and network perspectives , 2009, Nature Reviews Drug Discovery.

[42]  Zhihong Yang,et al.  Small G proteins as novel therapeutic targets in cardiovascular medicine. , 2003, News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society.

[43]  Hwa-Young Kim,et al.  Crystal structure of calcineurin–cyclophilin–cyclosporin shows common but distinct recognition of immunophilin–drug complexes , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[44]  S. Armstrong.  Protein kinase activation and myocardial ischemia/reperfusion injury. , 2004, Cardiovascular research.

[45]  Hong Chen,et al.  MECHANISMS UNDERLYING VASORELAXANT ACTION OF ASTRAGALOSIDE IV IN ISOLATED RAT AORTIC RINGS , 2007, Clinical and experimental pharmacology & physiology.

[46]  Rama S. Verma,et al.  An improved protocol for primary culture of cardiomyocyte from neonatal mice , 2008, In Vitro Cellular & Developmental Biology - Animal.

[47]  A. Kleber,et al.  Patterned growth of neonatal rat heart cells in culture. Morphological and electrophysiological characterization. , 1991, Circulation research.

[48]  Jeffrey Robbins,et al.  A Calcineurin-Dependent Transcriptional Pathway for Cardiac Hypertrophy , 1998, Cell.

[49]  K. Gunsalus,et al.  Network modeling links breast cancer susceptibility and centrosome dysfunction. , 2007, Nature genetics.

[50]  Rajendra K. Sharma,et al.  Involvement of Calcineurin in Ischemic Myocardial Damage , 2011 .

[51]  H. Katus,et al.  Novel molecular targets in the treatment of cardiac hypertrophy. , 2006, Recent patents on cardiovascular drug discovery.

[52]  C. Klee,et al.  Dual calcium ion regulation of calcineurin by calmodulin and calcineurin B. , 1994, Biochemistry.

[53]  R. Kloner,et al.  Potential Role of Renin-Angiotensin System Blockade for Preventing Myocardial Ischemia/Reperfusion Injury and Remodeling after Myocardial Infarction , 2011, Postgraduate medicine.

[54]  Roger Guimerà,et al.  Cartography of complex networks: modules and universal roles , 2005, Journal of statistical mechanics.

[55]  N. Frangogiannis.  The immune system and cardiac repair. , 2008, Pharmacological research.

[56]  Péter Csermely,et al.  The efficiency of multi-target drugs: the network approach might help drug design. , 2004, Trends in pharmacological sciences.

[57]  G. Parmigiani,et al.  Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses , 2008, Science.

[58]  R. Albert.  Scale-free networks in cell biology , 2005, Journal of Cell Science.

[59]  Peng Jiang,et al.  Molecular networks for the study of TCM Pharmacology , 2010, Briefings Bioinform..

[60]  Hiroaki Kitano,et al.  Biological robustness , 2008, Nature Reviews Genetics.

[61]  N. Pandya,et al.  Role of mitogen-activated protein (MAP) kinases in cardiovascular diseases. , 2006, Cardiovascular drug reviews.