title: Salvianolic acid B and tanshinone IIA attenuate myocardial ischemia injury in mice by NO production through multiple pathways.
abstract: OBJECTIVE
  Salvia miltiorrhiza (Danshen) has been widely used for the treatment of cardiac and cerebrovascular disease throughout history. The objective of this study is to further elucidate the mechanisms underlying Danshen's cardiac protective effects to support its clinical evidence.
  
  
  METHODS
  AND RESULTS: Salvianolic acid B (Sal B) and Tanshinone IIA (Tan IIA) are two of the major components in Danshen. We observed that Sal B and Tan IIA have cardioprotective effects in an in vivo myocardial infarction model of C57 mice, have vasodilator action in a ex vivo micro-artery system through the endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) pathway and are involved in the regulation of the L-arginine/eNOS/NO pathways in human umbilical vein endothelial cells (HUVECs). Both Sal B and Tan IIA inhibited cardiac hypertrophy and infarction sizes and improved cardiac function at 4 weeks after induction of infarction. Furthermore, an eNOS inhibitor (L-NAME) obliterated the observed effects. Sal B and Tan IIA mediated vasodilatation in mice coronaries ex vivo, the effect of which was decreased with either L-NAME or PI3K inhibitor (LY294002). In addition, Sal B and Tan IIA-induced vasodilatation was observed ex vivo in the microvessels of eNOS-/- mice. Sal B and Tan IIA also stimulated eNOS phosphorylation in a concentration- and time-dependent manner in the HUVEC culture, which was diminished by LY294002. In addition, Sal B and Tan IIA were found to stimulate the phosphorylation of AMPK (Thr(172)) and Akt (Ser(473)), while compound C significantly decreased the phosphorylation of Akt (Ser(473)) mediated by both. Finally, Sal B and Tan IIA were found to increase NO production, induce [(3)H]-L-arginine uptake and increase the CAT-1 and CAT-2B mRNA levels in HUVEC culture.
  
  
  CONCLUSIONS
  These findings suggest that both Sal B and Tan IIA have cardioprotective function in certain levels through multiple targets related with NO production, such as eNOS phosphorylation, L-arginine uptake and CAT expression, which may have major clinical implications.
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Chunshui
authors.initials: C
authors.lastname: Pan
authors.forename: Lixia
authors.initials: L
authors.lastname: Lou
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Huo
authors.forename: Gurbakhshish
authors.initials: G
authors.lastname: Singh
authors.forename: Meng
authors.initials: M
authors.lastname: Chen
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhang
authors.forename: Aiming
authors.initials: A
authors.lastname: Wu
authors.forename: Mingjing
authors.initials: M
authors.lastname: Zhao
authors.forename: Shuoren
authors.initials: S
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D045784:Abietanes / Q000494:pharmacology*; D026923:Amino Acid Transport Systems, Basic / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000378:metabolism; D001572:Benzofurans / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D027201:Cationic Amino Acid Transporter 1 / Q000235:genetics; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D053630:Depsides
chemical_list: D055372:AMP-Activated Protein Kinases; D045784:Abietanes; D026923:Amino Acid Transport Systems, Basic; D001120:Arginine; D001572:Benzofurans; D002317:Cardiovascular Agents; D027201:Cationic Amino Acid Transporter 1; D002867:Chromones; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D009025:Morpholines; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D058539:Phosphatidylinositol 3-Kinase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; C420825:SLC7A1 protein, human; C414177:SLC7A2 protein, human; C021751:tanshinone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C076944:salvianolic acid B; D053630:Depsides; C496314:NOS3 protein, human; C496315:Nos3 protein, mouse