title: Tongxinluo protects against pressure overload-induced heart failure in mice involving VEGF/Akt/eNOS pathway activation.
abstract: BACKGROUND
  It has been demonstrated that Tongxinluo (TXL), a traditional Chinese medicine compound, improves ischemic heart disease in animal models via vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). The present study aimed to investigate whether TXL protects against pressure overload-induced heart failure in mice and explore the possible mechanism of action.
  
  
  RESULTS
  Transverse aortic constriction (TAC) surgery was performed in mice to induce heart failure. Cardiac function was evaluated by echocardiography. Myocardial pathology was detected using hematoxylin and eosin or Masson trichrome staining. We investigated cardiomyocyte ultrastructure using transmission electron microscopy. Angiogenesis and oxidative stress levels were determined using CD31 and 8-hydroxydeoxyguanosine immunostaining and malondialdehyde assay, respectively. Fetal gene expression was measured using real-time PCR. Protein expression of VEGF, phosphorylated (p)-VEGF receptor 2 (VEGFR2), p-phosphatidylinositol 3-kinase (PI3K), p-Akt, p-eNOS, heme oxygenase-1 (HO-1), and NADPH oxidase 4 (Nox4) were measured with western blotting. Twelve-week low- and high-dose TXL treatment following TAC improved cardiac systolic and diastolic function and ameliorated left ventricular hypertrophy, fibrosis, and myocardial ultrastructure derangement. Importantly, TXL increased myocardial capillary density significantly and attenuated oxidative stress injury in failing hearts. Moreover, TXL upregulated cardiac nitrite content and the protein expression of VEGF, p-VEGFR2, p-PI3K, p-Akt, p-eNOS, and HO-1, but decreased Nox4 expression in mouse heart following TAC.
  
  
  CONCLUSIONS
  Our findings indicate that TXL protects against pressure overload-induced heart failure in mice. Activation of the VEGF/Akt/eNOS signaling pathway might be involved in TXL improvement of the failing heart.
authors.affiliation: Department of Traditional Chinese Medicine, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Institute of Pathogen Biology, Shandong University, Jinan, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Wen-wu
authors.initials: WW
authors.lastname: Bai
authors.affiliation: Department of Traditional Chinese Medicine, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Yi-fan
authors.initials: YF
authors.lastname: Xing
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Xiao-ting
authors.initials: XT
authors.lastname: Lu
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Yuan-yuan
authors.initials: YY
authors.lastname: Sun
authors.affiliation: Department of Traditional Chinese Medicine, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Yu-xia
authors.initials: YX
authors.lastname: Zhao
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006334:Heart Function Tests; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014463:Ultrasonography; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D004365:Drugs, Chinese Herbal; D042461:Vascular Endothelial Growth Factor A; C513941:tongxinluo; D000080242:8-Hydroxy-2'-Deoxyguanosine; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D003849:Deoxyguanosine