Vascular Smooth Muscle Cells: A Novel Cross-Talk in the Pathogenesis of Atherosclerosis Angiotensin II Enhances Interleukin-18 Mediated Inflammatory Gene Expression in

Vascular smooth muscle cells (VSMCs) express functional interleukin-18 receptors (IL-18Rs), composed of and subunits. These subunits are elevated in VSMCs of atherosclerotic plaques and can be induced by inflammatory agents in cultured VSMC. Because both IL-18 and Angiotensin II (Ang II) are implicated in atherosclerosis, our objective was to analyze the role of IL-18 signaling and potential cross-talk with Ang II in VSMC. We observed that IL-18 activated Src kinase, protein kinase C, p38 and JNK MAPKs, Akt kinase, transcription factors NF-kB and AP-1, and induced expression of pro-inflammatory cytokines in VSMC. Pretreatment of VSMC with Ang II enhanced IL-18-induced NF-kB activation and cytokine gene expression. Interestingly, Ang II directly increased mRNA and cell surface protein levels of the IL-18R subunit. Functional relevance in an organ culture model was demonstrated by the observation that incubation of intact mouse aortas ex vivo with Ang II also significantly increased IL-18R expression. Furthermore, Ang II significantly stimulated transcription from a minimal IL-18R promoter containing putative binding sites for STAT and AP-1. Ang II also increased in vivo recruitment of STAT-3 on the IL-18R promoter. Finally, dominant negative STAT-3 mutant blocked Ang II-induced IL-18R promoter activation in CHO cells overexpressing AT1a receptor and IL-18R mRNA expression in HVSMC. Thus, Ang II enhances IL-18 induced inflammatory genes by increasing IL-18R expression. These results illustrate a novel mechanism wherein Ang IImediated increases in inflammatory genes and proatherogenic effects in the vasculature are enhanced by a vicious loop and cross-talk with the IL-18 signaling pathway. (Circ Res. 2005;96:1064-1071.)