title: Genistein prevents hyperglycemia-induced monocyte adhesion to human aortic endothelial cells through preservation of the cAMP signaling pathway and ameliorates vascular inflammation in obese diabetic mice.
abstract: Hyperglycemia-induced vascular inflammation resulting in the enhanced monocyte-endothelial cell (EC) interaction is the key event in the pathogenesis of atherosclerosis in diabetes. Here, we investigated the effect of isoflavone genistein on hyperglycemia-stimulated vascular inflammation. Human aortic EC (HAEC) were pretreated with genistein before the addition of high glucose (HG; 25 mmol/L) for 48 h. Genistein at a physiological concentration (0.1 μmol/L) significantly inhibited HG-induced adhesion of monocytes to HAEC and suppressed endothelial production of monocyte chemotactic protein-1 (MCP-1) and IL-8. Inhibition of adenylate cyclase or protein kinase A (PKA) significantly attenuated the antiadhesion effect of genistein. Consistently, genistein improved HG-impaired intracellular cAMP production and PKA activity in HAEC. Six-week-old diabetic db/db mice were untreated (db/db) or treated with a diet containing 1 g genistein/kg diet (db/db+G) for 8 wk. Their nondiabetic db/+ mice were used as normal controls. Circulating concentrations of MCP-1/JE and KC were significantly greater, whereas IL-10 concentrations were lower in db/db mice than those in normal mice. Dietary supplementation of genistein did not normalize but significantly suppressed the elevated serum concentrations of MCP-1/JE from 286 ± 30 ng/L to 181 ± 35 ng/L and KC from 321 ± 21 ng/L to 232 ± 20 ng/L while increasing that of IL-10 from 35 ± 4 ng/L to 346 ± 35 ng/L in db/db+G mice. Further, genistein treatment suppressed diabetes-induced adhesion of monocytes to EC by 87% and endothelial secretion of adhesion molecules. We conclude that genistein improves diabetes-caused vascular inflammation, which may be mediated through promoting the cAMP/PKA pathway.
authors.affiliation: Department of Human Nutrition, Foods and Exercise, College of Agriculture and Life Sciences, Virginia Tech, Blacksburg, VA, USA.
authors.forename: Pon Velayutham Anandh
authors.initials: PV
authors.lastname: Babu
authors.forename: Hongwei
authors.initials: H
authors.lastname: Si
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Fu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhen
authors.forename: Dongmin
authors.initials: D
authors.lastname: Liu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001011:Aorta / Q000166:cytology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000178:diet therapy* / Q000276:immunology / Q000503:physiopathology; D019587:Dietary Supplements; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019833:Genistein / Q000627:therapeutic use*; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009000:Monocytes / Q000187:drug effects; D009765:Obesity / Q000150:complications / Q000178:diet therapy* / Q000276:immunology / Q000503:physiopathology; D015290:Second Messenger Systems / Q000187:drug effects; D014657:Vasculitis / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004791:Enzyme Inhibitors; D019833:Genistein; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases