title: Stat3-dependent acute Rantes production in vascular smooth muscle cells modulates inflammation following arterial injury in mice.
abstract: Inflammation is a key component of arterial injury, with VSMC proliferation and neointimal formation serving as the final outcomes of this process. However, the acute events transpiring immediately after arterial injury that establish the blueprint for this inflammatory program are largely unknown. We therefore studied these events in mice and found that immediately following arterial injury, medial VSMCs upregulated Rantes in an acute manner dependent on Stat3 and NF-kappaB (p65 subunit). This led to early T cell and macrophage recruitment, processes also under the regulation of the cyclin-dependent kinase inhibitor p21Cip1. Unique to VSMCs, Rantes production was initiated by Tnf-alpha, but not by Il-6/gp130. This Rantes production was dependent on the binding of a p65/Stat3 complex to NF-kappaB-binding sites within the Rantes promoter, with shRNA knockdown of either Stat3 or p65 markedly attenuating Rantes production. In vivo, acute NF-kappaB and Stat3 activation in medial VSMCs was identified, with acute Rantes production after injury substantially reduced in Tnfa-/- mice compared with controls. Finally, we generated mice with SMC-specific conditional Stat3 deficiency and confirmed the Stat3 dependence of acute Rantes production by VSMCs. Together, these observations unify inflammatory events after vascular injury, demonstrating that VSMCs orchestrate the arterial inflammatory response program via acute Rantes production and subsequent inflammatory cell recruitment.
authors.affiliation: Translational Medicine Branch, National Heart, Lung, and Blood Institute/NIH, Bethesda, MD 20892, USA
authors.forename: Jason C
authors.initials: JC
authors.lastname: Kovacic
authors.forename: Rohit
authors.initials: R
authors.lastname: Gupta
authors.forename: Angela C
authors.initials: AC
authors.lastname: Lee
authors.forename: Mingchao
authors.initials: M
authors.lastname: Ma
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.forename: Claire N
authors.initials: CN
authors.lastname: Tolbert
authors.forename: Avram D
authors.initials: AD
authors.lastname: Walts
authors.forename: Leilani E
authors.initials: LE
authors.lastname: Beltran
authors.forename: Hong
authors.initials: H
authors.lastname: San
authors.forename: Guibin
authors.initials: G
authors.lastname: Chen
authors.forename: Cynthia
authors.initials: C
authors.lastname: St Hilaire
authors.forename: Manfred
authors.initials: M
authors.lastname: Boehm
mesh_terms: D000818:Animals; D001158:Arteries / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D018946:Chemokine CCL5 / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis / Q000235:genetics / Q000502:physiology; D005260:Female; D015850:Interleukin-6 / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014657:Vasculitis / Q000209:etiology*
chemical_list: C491768:Ccl2 protein, mouse; C493957:Cdkn1a protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014409:Tumor Necrosis Factor-alpha