TNF-α induces endothelial dysfunction via PKC-ζ-dependent NADPH oxidase activation.
Endothelial dysfunction is implicated in a variety of cardiovascular diseases although the detailed mechanisms are not yet completely understood. A relationship has been suggested to exist between inflammation and endothelial dysfunction. TNF-α serves as one of the most important pro-inflammatory cytokines. The main objectives of the present study were to explore the effect of PKC-ζ on TNF-α-impaired endothelial function as well as the underlying mechanisms. Acetylcholine-induced endothelium-dependent vasodilation of mouse thoracic aorta stimulated by TNF-α was initially determined. PKC-ζ deficient mice and the specific inhibitor of NADPH oxidase were respectively applied to elucidate their roles in TNF-α-induced endothelial dysfunction. In vitro superoxide generation in HAECs was detected by DHE staining after administration of TNF-α. Meanwhile, the regulatory p47(phox) subunit of NADPH oxidase was evaluated by Western blotting and RT-PCR. The results showed that TNF-α conspicuously impaired endothelium-dependent vasodilation and the impairment was attenuated by either depleting PKC-ζ or inhibiting NADPH oxidase. In vitro TNF-α increased superoxide production and p47(phox) expression in HAECs, and such increases could be ameliorated by the specific PKC-ζ inhibitor. Our findings suggest that superoxide over-production triggered by PKC-ζ-dependent NADPH oxidase activation contributes to TNF-α-induced endothelial dysfunction.
Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Yi
Y
Huang
Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Li
L
Yan
Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. songrong@hotmail.com.|Department of Nephrology, Hannover Medical School, Hannover, 30625, Germany. songrong@hotmail.com.
Song
S
Rong
Department of Nephrology, Hannover Medical School, Hannover, 30625, Germany.
Hermann
H
Haller
Department of Nephrology, Hannover Medical School, Hannover, 30625, Germany.
Torsten
T
Kirch
D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism*; D008297:Male; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000099221:Protein Kinase C zeta
D019255:NADPH Oxidases; D011493:Protein Kinase C; D014409:Tumor Necrosis Factor-alpha; D000099221:Protein Kinase C zeta