Inhibiting adhesion events by Panax notoginseng saponins and Ginsenoside Rb1 protecting arteries via activation of Nrf2 and suppression of p38 - VCAM-1 signal pathway.
BACKGROUND
Asian countries, such as China, Japan, and Korea, have witnessed a history of more than 1000 years of Panax notoginseng (Burk.) F.H. Chen's application as a famous traditional medicine for cardiovascular diseases (Zhou et al., 2004). The use of Panax notoginseng (Sanqi) was first recorded in "Bencao Gangmu", which was written by Li Shizhen, a Chinese pharmacologist of the MING dynasty, in 1578. It is included in "The Plant List" as one species of genus Panax (family Araliaceae). Panax notoginseng saponins (PNS) are the major active ingredients extracted from Panax notoginseng.


OBJECTIVE
This study investigated whether PNS and the active constituent Ginsenoside Rb1 inhibits adhesion events by regulating the NF-E2-related factor 2 (Nrf2) - p38 - vascular cell adhesion molecule (VCAM)-1 pathway.


METHODS
The AS model rats were treated once daily with PNS (100mg/kg, i.p.) or Rb1 (40mg/kg, i.p.), and pathological changes in the aortas were observed by electron microscopy and Sudan IV staining. The serum levels of NO, superoxide dismutase (SOD) and TNF-α were measured. Upon treatment with H2O2to induce oxidative stress,cell viability and LDH levels were measured after cells were cultured with PNS or Rb1. oxidized low density lipoprotein (oxLDL)-induced VCAM-1 and p38 protein expression and THP1 cell adhesion to ECs were assessed after treatment with PNS or Rb1. Nuclear translocation of Nrf2 and expression of its target protein heme oxygenase (HO)-1 were observed in the respective presence of PNS or Rb1.


RESULTS
Upon treatment with PNS or Rb1, pathological changes observed in the aortas of AS model rats were alleviated, and an increase in serum levels of NO and SOD and a decrease in TNF-α levels were observed. In vitro treatment with PNS or Rb1 protected endothelial cells (ECs) from H2O2-mediated cytotoxicity, suppressed oxLDL-induced p38 and VCAM-1 protein expression and inhibited THP1 cell adhesion to ECs. Finally, PNS and Rb1 treatment functionally activated Nrf2 in ECs.


CONCLUSIONS
Nrf2, an EC protective system, suppresses monocyte adhesion events via the inhibition of the ROS - TNF-α - p38 - VCAM-1 pathway following treatment with PNS, with Rb1 specifically playing an important role among PNS active components.
Department of Pharmacy, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China.
Jishan
J
Fan
Department of Ophthalmology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
Danning
D
Liu
Department of Pharmacy, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China.
Cuiyao
C
He
Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China. Electronic address: river080@sohu.com.
Xiaohui
X
Li
Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Third Military Medical University, Chongqing 400038, China. Electronic address: steven2535@sina.com.
Fengtian
F
He
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D001018:Aortic Diseases / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018920:Coculture Techniques; D019610:Cytoprotection / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification / Q000494:pharmacology*; D036145:Ginsenosides / Q000302:isolation & purification / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009569:Nitric Oxide / Q000097:blood; D053723:Panax notoginseng / Q000737:chemistry*; D008517:Phytotherapy; D010946:Plants, Medicinal; D017208:Rats, Wistar; D012503:Saponins / Q000302:isolation & purification / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*; D015054:Zymosan; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D004365:Drugs, Chinese Herbal; D036145:Ginsenosides; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495637:Nfe2l2 protein, rat; C519374:Panax notoginseng extract; D012503:Saponins; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D009569:Nitric Oxide; C442759:ginsenoside Rb1; D015054:Zymosan; D013482:Superoxide Dismutase; D048051:p38 Mitogen-Activated Protein Kinases
Endothelial cells; Ginsenoside Rb1 (PubChem CID: 9898279); Hydrogen peroxide (PubChem CID: 784); Nrf2; P38; Panax notoginseng saponins; Rb1; Sulforaphane (PubChem CID: 5350); VCAM-1