Angiotensin II enhances AT 1-Nox1 binding and stimulates arterial smooth muscle cell migration and proliferation through AT 1, Nox1, and interleukin-18

Anthony J. Valente, Tadashi Yoshida, Subramanyam N. Murthy, Siva S.V.P. Sakamuri, Masato Katsuyama, Robert A. Clark, Patrice Delafontaine, Bysani Chandrasekar

Research output: Contribution to journalArticlepeer-review

85 Scopus citations


The redox-sensitive transcription factors NF-κB and activator protein-1 (AP-1) are critical mediators of ANG II signaling. The promitogenic and promigratory factor interleukin (IL)-18 is an NF-κB- and AP-1-responsive gene. Therefore, we investigated whether ANG II-medi-ated smooth muscle cell (SMC) migration and proliferation involve IL-18. ANG II induced rat carotid artery SMC migration and proliferation and IL-18 and metalloproteinase (MMP)-9 expression via ANG II type 1 (AT 1) receptor. ANG II-induced superoxide generation, NF-κB and AP-1 activation, and IL-18 and MMP-9 induction were all markedly attenuated by losartan, diphenyleneiodonium chloride (DPI), and Nox1 knockdown. Similar to ANG II, addition of IL-18 also induced superoxide generation, activated NF-κB and AP-1, and stimulated SMC migration and proliferation, in part via Nox1, and both ANG II and IL-18 induced NOX1 transcription in an AP-1-dependent manner. AT 1 physically associates with Nox1 in SMC, and ANG II enhanced this binding. Interestingly, exogenous IL-18 neither induced AT 1 binding to Nox1 nor enhanced the ANG II-induced increase in AT 1/Nox1 binding. Importantly, IL-18 knockdown, or pretreatment with IL-18 neutralizing antibodies, or IL-18 binding protein, all attenuated the migratory and mitogenic effects of ANG II. Continuous infusion of ANG II for 7 days induced carotid artery hyperplasia in rats via AT 1 and was associated with increased AT 1/ Nox1 binding (despite lower AT 1 levels); increased DPI-inhibitable superoxide production; increased phospho-IKK(β, JNK, p65, and c-Jun; and induction of IL-18 and MMP-9 in endothelium-denuded carotid arteries. These results indicate that IL-18 amplifies the ANG II-induced, redox-dependent inflammatory cascades by activating similar promitogenic and promigratory signal transduction pathways. The ANG II/Nox1/IL-18 pathway may be critical in hyperplastic vascular diseases, including atherosclerosis and restenosis.

Original languageEnglish (US)
Pages (from-to)282-296
Number of pages15
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number3
StatePublished - Aug 1 2012


  • Angiotensin II type 1 receptor
  • Atherosclerosis
  • Migration
  • Mitogenesis
  • Renin-angiotensin-aldosterone system
  • Restenosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology


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