Beneficial effects of antioxidants and L-arginine on oxidation-sensitive gene expression and endothelial NO synthase activity at sites of disturbed shear stress.
Atherogenesis is enhanced in arterial segments exposed to disturbed blood flow, indicating the active participation of the hemodynamic environment in lesion formation. Turbulent shear stress selectively regulates responsive genes in the endothelium and increases the damage induced by free radicals. The purpose of the present study was to evaluate the effects of intervention with antioxidants and l-arginine on endothelial NO synthase (eNOS) and oxidation-sensitive gene perturbation induced by disturbed flow in vitro and in vivo. Both human endothelial cells exposed to shear stress and high atherosclerosis-prone areas of hypercholesterolemic low-density lipoprotein receptor knockout (LDLR(-/-)) mice showed increased activities of redox-transcription factors (ELK-1, p-Jun, and p-CREB) and decreased expression of eNOS. Intervention with antioxidants and l-arginine reduced the activation of redox-transcription factors and increased eNOS expression in cells and in vivo. These results demonstrate that atherogenic effects induced by turbulent shear stress can be prevented by cotreatment with antioxidants and l-arginine. The therapeutic possibility to modulate shear stress-response genes may have important implications for the prevention of atherosclerosis and its clinical manifestations.
de Nigris
Filomena
F
Department of Medicine-0682, University of California, San Diego, CA 92093, USA.
Lerman
Lilach O
LO
Ignarro
Sharon Williams
SW
Sica
Giacomo
G
Lerman
Amir
A
Palinski
Wulf
W
Ignarro
Louis J
LJ
Napoli
Claudio
C
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001120:Arginine / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000517:prevention & control; D015153:Blotting, Western; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D004730:Endothelium, Vascular / Q000166:cytology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics* / Q000502:physiology; D013314:Stress, Mechanical; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D050807:ets-Domain Protein Elk-1
D000975:Antioxidants; C115163:CREB1 protein, human; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; C494113:Elk1 protein, mouse; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D011973:Receptors, LDL; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D001120:Arginine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D010100:Oxygen