Angiotensin II promotes the inflammatory response to CD40 ligation via TRAF-2.
A plethora of evidence supports a link between inflammation and atherogenesis. Both the vasoactive peptide angiotensin II (ANG II) as well as the CD40/CD154 signaling pathway exhibit proinflammatory properties with a direct influence on atherogenesis. We therefore tested the hypothesis that ANG II interacts with CD40/CD154 in human vascular smooth muscle cells (SMC). ANG II did not increase expression of CD40 in human SMC. However, when SMC were prestimulated with ANG II and thereafter stimulated with CD154, the ligand for CD40, the release of IL-6 as a marker of inflammatory activation was augmented compared to cells not primed with ANG II. TNF receptor-associated factor 2 (TRAF-2), an important adaptor protein involved in CD40 signaling, but not TRAF-5 or -6, was increased by ANG II via activation of the angiotensin II type 1 (AT1) receptor subtype. These results suggest that a signaling pathway downstream of CD40 may be altered by ANG II prestimulation. Thus, ANG II can also indirectly cause inflammatory activation of vascular SMC. The data show a novel link between the proatherogenic vasoactive peptide ANG II and cell-cell contact-mediated inflammatory pathways and implicate options for the prevention and therapy of atherosclerotic disease.
Ruef
Johannes
J
Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
Browatzki
Michael
M
Pfeiffer
Caroline A H
CA
Schmidt
Joachim
J
Kranzhöfer
Roger
R
D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D050197:Atherosclerosis / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D020239:Receptor Cross-Talk; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012501:Saphenous Vein / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D015854:Up-Regulation
D047228:Angiotensin II Type 1 Receptor Blockers; D019013:CD40 Antigens; D015850:Interleukin-6; D044140:Receptor, Angiotensin, Type 1; D047992:TNF Receptor-Associated Factor 2; D000804:Angiotensin II; D023201:CD40 Ligand; D019808:Losartan