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

• Published in: Circulation research Vol. 96; no. 10; pp. 1064 - 1071
• Main Authors: Sahar, Saurabh, Dwarakanath, Roopashree S, Reddy, Marpadga A, Lanting, Linda, Todorov, Ivan, Natarajan, Rama
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 27.05.2005; Lippincott
• Subjects: Angiotensin II - pharmacology; Animals; Arteriosclerosis - etiology; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; DNA-Binding Proteins - physiology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Humans; Inflammation - genetics; Interleukin-18 - pharmacology; Interleukin-18 Receptor alpha Subunit; Medical sciences; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Promoter Regions, Genetic; Receptor, Angiotensin, Type 1 - physiology; Receptors, Interleukin - genetics; Receptors, Interleukin-18; STAT3 Transcription Factor; Trans-Activators - physiology; Transcriptional Activation; Vertebrates: cardiovascular system; Pathogenesis; Peptide hormone; Cytokine; NF-kB; Cardiovascular disease; Smooth muscle; Gene expression; Interleukin 18; Vascular disease; Octapeptide; Renin angiotensin system; Vertebrata; Mammalia; interleukin-18; Atherosclerosis; cytokines; Circulatory system; Transcription factor NFκB; Angiotensin II; vascular smooth muscle cells
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000168210.10358.f4

Vascular smooth muscle cells (VSMCs) express functional interleukin-18 receptors (IL-18Rs), composed of α and β 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-18Rα 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-18Rα expression. Furthermore, Ang II significantly stimulated transcription from a minimal IL-18Rα promoter containing putative binding sites for STAT and AP-1. Ang II also increased in vivo recruitment of STAT-3 on the IL-18Rα promoter. Finally, dominant negative STAT-3 mutant blocked Ang II-induced IL-18Rα promoter activation in CHO cells overexpressing AT1a receptor and IL-18Rα mRNA expression in HVSMC. Thus, Ang II enhances IL-18 induced inflammatory genes by increasing IL-18Rα 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.