title: A novel Danshensu derivative confers cardioprotection via PI3K/Akt and Nrf2 pathways.
abstract: BACKGROUND
  Danshensu (3-(3,4-dihydroxyphenyl) lactic acid, DSS) is one of the most promising cardioprotective components in the root of Salvia miltiorrhiza but its poor chemical stability poses hurdles in its therapeutic development. It is therefore desirable to enhance the stability of DSS by chemical modification to improve its activities. In the present study, a novel DSS derivative named ADTM was synthesized and characterized for its cardioprotective properties.
  
  
  METHODS
  Oxidative stress was induced in H9c2 cardiomyoblast cells by tert-butylhydroperoxide (t-BHP) and the protective effects of ADTM were evaluated. For in vivo study, adult rats were treated with vehicle, DSS, ADTM or amlodipine (n=6-8/group) for 24h before the induction of acute myocardial ischemia. At the end of each experiment, infarct size was measured. Underlying the mechanisms of the cardioprotective effects of ADTM were further investigated in H9c2 cells and rat myocardium by evaluating the effects of Nrf2 (NF-E2-related factor 2) and Akt/PI3K pathways.
  
  
  RESULTS
  ADTM was approximately 10 times more effective than DSS against t-BHP-induced cell injury in H9c2 cells. In rat myocardial ischemia model, ADTM treatment significantly alleviated myocardial infarction. Akt/PI3K and Nrf2 pathways were demonstrated to be involved in both in vitro and in vivo experiments.
  
  
  CONCLUSIONS
  These results demonstrated that ADTM displayed much better cardioprotective effects than its parent compounds both in vitro and in vivo. This cardioprotection is mediated, at least in part, through Akt/PI3K and Nrf2 pathways. This novel compound represents a promising candidate for the treatment of cardiovascular diseases (CVDs), particularly myocardial infarction.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine (University of Macau), Avenue Padre Tomás Pereira S.J., Macao SAR, China; Institute of Chinese Medical Sciences, University of Macau, Avenue Padre Tomás Pereira S.J., Taipa, Macao SAR, China.
authors.forename: Guozhen
authors.initials: G
authors.lastname: Cui
authors.forename: Luchen
authors.initials: L
authors.lastname: Shan
authors.forename: Mingwai
authors.initials: M
authors.lastname: Hung
authors.forename: Siwai
authors.initials: S
authors.lastname: Lei
authors.forename: Inleng
authors.initials: I
authors.lastname: Choi
authors.forename: Zaijun
authors.initials: Z
authors.lastname: Zhang
authors.forename: Pei
authors.initials: P
authors.lastname: Yu
authors.forename: Puiman
authors.initials: P
authors.lastname: Hoi
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Wang
authors.forename: Simon Mingyuen
authors.initials: SM
authors.lastname: Lee
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D007773:Lactates / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D002316:Cardiotonic Agents; D007773:Lactates; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; C035055:3,4-dihydroxyphenyllactic acid; D058539:Phosphatidylinositol 3-Kinase; D051058:Oncogene Protein v-akt
keywords: Cardioprotection; Danshensu derivative; Ischemia; Nrf2; Oxidative stress