title: Luhong formula inhibits myocardial fibrosis in a paracrine manner by activating the gp130/JAK2/STAT3 pathway in cardiomyocytes.
abstract: BACKGROUND
  Luhong formula (LHF)-a traditional Chinese medicine containing Cervus nippon Temminck, Carthamus tinctorius L., Cinnamomum cassia Presl, Codonopisis pilosula( Franch.) Nannf., Astragalus membranaceus ( Fisch.) Bge. var. mongholicus ( Bge.) Hsiao, Lepidium apetalum Willd-is used in the treatment of heart failure.
  
  
  OBJECTIVE
  To investigate the antifibrotic efficacy of LHF in a myocardial infarction-induced rat model of heart failure and to determine its mechanism of action.
  
  
  METHODS
  Myocardial infarction was induced in rats by coronary artery ligation, and cardiac fibroblasts were isolated. Neonatal rat cardiomyocytes (NRCMs) were isolated from 2 to 3-day-old Sprague-Dawley male rats, and cardiomyocyte hypertrophy was induced by isoprenaline. Histological examination was carried out to estimate the degree of myocardial fibrosis. Expression of gp130/JAK2/STAT3 pathway proteins was measured by western blot. The mRNA levels of downstream genes of gp130/JAK2/STAT3 pathway (i.e., CTGF, TSP-1, and TIMP1) were determined by RT-PCR; while CTGF, TSP-1, and TIMP1 protein levels were measured by ELISA. To investigate paracrine effects, cell proliferation and collagen synthesis was measured after treating cardiac fibroblasts with the conditioned media from isoprenaline-treated NRCMs.
  
  
  RESULTS
  Histopathological changes showed that LHF inhibited myocardial fibrosis in heart failure rats. Treatment with LHF up-regulated gp130, JAK2, and STAT3 protein expression in heart tissue, and down-regulated CTGF, TSP-1, and TIMP1 gene expression. Isoprenaline-treated NRCMs displayed lower expression of the gp130, JAK2, and STAT3 pathway proteins and higher secretion of its downstream signaling molecules (CTGF, TSP-1, TIMP1). LHF inhibited cardiac fibroblast proliferation and collagen synthesis after treatment with the conditioned media from isoprenaline-treated NRCMs.
  
  
  CONCLUSIONS
  LHF treatment attenuates myocardial fibrosis in vivo. LHF inhibits cardiac fibroblasts proliferation and collagen synthesis in a paracrine manner by activating the gp130/JAK2/STAT3 pathway in cardiomyocytes, thereby inhibiting the secretion of downstream profibrogenic cytokines.
authors.affiliation: Department of Cardiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Huiyan
authors.initials: H
authors.lastname: Qu
authors.affiliation: Department of Cardiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Cardiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Cardiology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: zhouhuam@hotmail.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D050822:Cytokine Receptor gp130 / Q000187:drug effects; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005355:Fibrosis; D006333:Heart Failure / Q000188:drug therapy; D053614:Janus Kinase 2 / Q000187:drug effects; D051907:Lysosomal Membrane Proteins / Q000187:drug effects; D008297:Male; D008516:Medicine, Chinese Traditional; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D019899:Paracrine Communication / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D012844:Sincalide / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D050822:Cytokine Receptor gp130; D004365:Drugs, Chinese Herbal; D053614:Janus Kinase 2; D051907:Lysosomal Membrane Proteins; D050796:STAT3 Transcription Factor; D012844:Sincalide; C489117:Lamp1 protein, rat; D052118:Lysosomal-Associated Membrane Protein 1; C494088:Stat3 protein, rat; C000621892:luhong; C507927:Jak2 protein, rat
keywords: Cardiovascular system; Cytokines; Fibroblast; Gene expression; Heart failure; Myocardial fibrosis; Myocardial infarction; Proliferation; Signal transduction; Traditional Chinese medicine