title: Hydroxysafflor yellow A promotes neovascularization and cardiac function recovery through HO-1/VEGF-A/SDF-1α cascade.
abstract: OBJECTIVE
  The present study was to investigate the proangiogenic and cardioprotective effects of hydroxysafflor yellow A (HSYA) against myocardial infarction (MI) injury and the underlying mechanisms.
  
  
  METHODS
  MI model was induced by ligation of the left coronary artery in normal and heme oxygenase-1 (HO-1) knockout mice and the ones receiving vascular endothelial growth factor-A (VEGF-A) or stromal cell-derived factor-1α (SDF-1α) antagonists. They were treated with three doses or single dose of HSYA for 28days. The cardiac function, endothelial progenitor cells (EPCs) mobilization, angiogenesis, the expression of HO-1, VEGF-A, SDF-1α and apoptosis or fibrosis related proteins in the peri-infarct area were evaluated at respective times. We further examined the effect of HSYA on EPCs CXC chemokiner receptor 4 (CXCR4) expression and the role of SDF-1α on EPCs function in vitro.
  
  
  RESULTS
  HSYA could dose dependently reduce left ventricular function impairment, myocardial apoptosis and fibrosis, and promote EPCs mobilization and myocardial neovascularization. Further, HO-1 knockout abolished HSYA-induced up-regulation of HO-1, VEGF-A and SDF-1α. VEGF antagonist significantly reduced HSYA-increased VEGF-A and SDF-1α levels and SDF-1 antagonist abolished HSYA-simulated up-regulation of SDF-1α. Meanwhile, HO-1 knockout, administration of VEGF and SDF-1 antibodies abrogated HSYA-promoted expression of the marker proteins of newborn microvessels and cardiac functional recovery. In vitro, HSYA dose dependently promoted (CXCR4) expression on EPCs. SDF-1α significantly accelerated EPCs function which was reversed by CXCR4 antagonist.
  
  
  CONCLUSIONS
  HSYA could promote EPCs function through the HO-1/VEGF-A/SDF-1α signaling cascade, which contributed largely to myocardial neovascularization and further improved cardiac function in MI mice.
authors.affiliation: Department of Pharmacy, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors.forename: Guo
authors.initials: G
authors.lastname: Wei
authors.affiliation: Department of Pharmacy, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Pharmacy, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors.forename: Jialin
authors.initials: J
authors.lastname: Duan
authors.affiliation: Department of Pharmacy, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Pharmacy, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Pharmacy, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China. Electronic address: miaomiaoxi2014@163.com.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Xi
authors.affiliation: Department of Pharmacy, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China. Electronic address: adwen-2004@hotmail.com.
authors.forename: Aidong
authors.initials: A
authors.lastname: Wen
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002599:Chalcone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D054377:Chemokine CXCL12 / Q000378:metabolism*; D066026:Endothelial Progenitor Cells / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006334:Heart Function Tests / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D019718:Receptors, CXCR4 / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D054377:Chemokine CXCL12; D011809:Quinones; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; C085278:hydroxysafflor yellow A; D002599:Chalcone; D051547:Heme Oxygenase-1
keywords: Endothelial progenitor cells; Hydroxysafflor yellow a; Myocardial infarction; Neovascularization