Plant Natural Products Calycosin and Gallic Acid Synergistically Attenuate Neutrophil Infiltration and Subsequent Injury in Isoproterenol-Induced Myocardial Infarction: A Possible Role for Leukotriene B4 12-Hydroxydehydrogenase?
Leukotriene B4 12-hydroxydehydrogenase (LTB4DH) catalyzes the oxidation of proinflammatory LTB4 into less bioactive 12-oxo-LTB4. We recently discovered that LTB4DH was induced by two different natural products in combination. We previously isolated gallic acid from Radix Paeoniae through a bioactivity-guided fractionation procedure. The purpose of this study is to test the hypothesis that LTB4DH inducers may suppress neutrophil-mediated inflammation in myocardial infarction. We first isolated the active compound(s) from another plant, Radix Astragali, by the similar strategy. By evaluating LTB4DH induction, we identified calycosin and formononetin from Radix Astragali by HPLC-ESI-MS technique. We confirmed that gallic acid and commercial calycosin or formononetin could synergistically induce LTB4DH expression in HepG2 cells and human neutrophils. Moreover, calycosin and gallic acid attenuated the effects of LTB4 on the survival and chemotaxis of neutrophil cell culture. We further demonstrated that calycosin and gallic acid synergistically suppressed neutrophil infiltration and protected cardiac integrity in the isoproterenol-induced mice model of myocardial infarction. Calycosin and gallic acid dramatically suppressed isoproterenol-induced increase in myeloperoxidase (MPO) activity and malondialdehyde (MDA) level. Collectively, our results suggest that LTB4DH inducers (i.e., calycosin and gallic acid) may be a novel combined therapy for the treatment of neutrophil-mediated myocardial injury.
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pok Fu Lam, Hong Kong.
Yuanyuan
Y
Cheng
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pok Fu Lam, Hong Kong.
Jia
J
Zhao
Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pok Fu Lam, Hong Kong.
Hung Fat
HF
Tse
Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, 10-102 Clinical Sciences Building, University of Alberta, Edmonton, Alberta, Canada T6G 2G3.
X Chris
XC
Le
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pok Fu Lam, Hong Kong.
Jianhui
J
Rong
D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D027883:Astragalus Plant / Q000737:chemistry / Q000378:metabolism; D001688:Biological Products / Q000494:pharmacology / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004357:Drug Synergism; D005707:Gallic Acid / Q000032:analysis / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D007529:Isoflavones / Q000032:analysis / Q000494:pharmacology / Q000627:therapeutic use*; D007545:Isoproterenol / Q000633:toxicity; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D009203:Myocardial Infarction / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D029596:Paeonia / Q000737:chemistry / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization
D001688:Biological Products; D007529:Isoflavones; C121707:7,3'-dihydroxy-4'-methoxyisoflavone; D008315:Malondialdehyde; D005707:Gallic Acid; D000429:Alcohol Oxidoreductases; C082646:leukotriene B4 12-hydroxydehydrogenase; D009195:Peroxidase; D007545:Isoproterenol