title: Angiotensin II enhances interleukin-18 mediated inflammatory gene expression in vascular smooth muscle cells: a novel cross-talk in the pathogenesis of atherosclerosis.
abstract: Vascular smooth muscle cells (VSMCs) express functional interleukin-18 receptors (IL-18Rs), composed of alpha and beta 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-18Ralpha 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-18Ralpha expression. Furthermore, Ang II significantly stimulated transcription from a minimal IL-18Ralpha promoter containing putative binding sites for STAT and AP-1. Ang II also increased in vivo recruitment of STAT-3 on the IL-18Ralpha promoter. Finally, dominant negative STAT-3 mutant blocked Ang II-induced IL-18Ralpha promoter activation in CHO cells overexpressing AT1a receptor and IL-18Ralpha mRNA expression in HVSMC. Thus, Ang II enhances IL-18 induced inflammatory genes by increasing IL-18Ralpha expression. These results illustrate a novel mechanism wherein Ang II- mediated 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.
authors.affiliation: Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, Calif 91010, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Sahar
authors.forename: Roopashree S
authors.initials: RS
authors.lastname: Dwarakanath
authors.forename: Marpadga A
authors.initials: MA
authors.lastname: Reddy
authors.forename: Linda
authors.initials: L
authors.lastname: Lanting
authors.forename: Ivan
authors.initials: I
authors.lastname: Todorov
authors.forename: Rama
authors.initials: R
authors.lastname: Natarajan
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology*; D004268:DNA-Binding Proteins / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D020382:Interleukin-18 / Q000494:pharmacology*; D053727:Interleukin-18 Receptor alpha Subunit; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D018123:Receptors, Interleukin / Q000235:genetics; D053724:Receptors, Interleukin-18; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000502:physiology; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; C508572:IL18R1 protein, human; C508573:Il18r1 protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D044140:Receptor, Angiotensin, Type 1; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D000804:Angiotensin II