Dipyridamole suppresses high glucose-induced osteopontin secretion and mRNA expression in rat aortic smooth muscle cells.
BACKGROUND
Diabetic patients are frequently afflicted with medial artery calcification, a predictor of cardiovascular mortality. Diabetes induced the expression of osteopontin in arterial vasculature, which is an indicator of disease progression in artery calcification and vascular stiffness. Signal transduction and strategies that suppress high glucose-induced osteopontin expression in arterial vascular smooth muscle cells is investigated.


RESULTS
The incubation of rat aortic smooth muscle cells under high glucose concentration increased osteopontin protein secretion and mRNA expression. Treatment with dipyridamole decreased high glucose-induced osteopontin expression and secretion. Dipyridamole decreased glucose-induced osteopontin through inhibition of phosphodiesterase, thereby increasing intracellular levels of adenosine-3',5'-cyclic monophosphate (cAMP) and guanosine-3',5'-cyclic monophosphate (cGMP), and increased thioredoxin expression to inhibit the reactive oxygen species (ROS) system. Induction of osteopontin was reversed when cells were pretreated with N-[2-bromocinnamyl(amino)ethyl]-5-isoquinolinesulfonamide (H89, cAMP-dependent protein kinase inhibitor), KT5823 (cGMP-dependent protein kinase inhibitor), or dinitrochlorobenzene (thioredoxin reductase inhibitor). The antioxidant, N-acetyl-L-cysteine, suppressed glucose-induced osteopontin expression by decreasing ROS concentration. Both H89 and KT5823 downregulated thioredoxin expression.


CONCLUSIONS
These results suggest a novel effect for dipyridamole to suppress high glucose-induced osteopontin protein secretion and mRNA expression. Dipyridamole has antioxidant properties and a phosphodiesterase inhibitor activity, which might be useful to ameliorate diabetic vasculopathy and its cardiovascular complications.
Hsieh
Ming-Song
MS
Department of Laboratory Medicine, Shuang-Ho Hospital, Taiwan.
Zhong
Wen-Bin
WB
Yu
Shu-Chuan
SC
Lin
John Yi-Chung
JY
Chi
Wei-Ming
WM
Lee
Horng-Mo
HM
D000818:Animals; D000975:Antioxidants; D001011:Aorta / Q000166:cytology*; D015415:Biomarkers / Q000032:analysis; D002114:Calcinosis; D002478:Cells, Cultured; D003925:Diabetic Angiopathies; D004176:Dipyridamole / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D053495:Osteopontin / Q000032:analysis / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D015415:Biomarkers; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D053495:Osteopontin; D004176:Dipyridamole; D005947:Glucose