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

作者：Valente Anthony J; Yoshida Tadashi; Murthy Subramanyam N; Sakamuri Siva S V P; Katsuyama Masato; Clark Robert A; Delafontaine Patrice; Chandrasekar Bysani^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2012, 303(3): H282-H296.

DOI：10.1152/ajpheart.00231.2012

• renin-angiotensin-aldosterone system
• mitogenesis
• migration
• atherosclerosis
• restenosis
• angiotensin II type 1 receptor

Valente AJ, Yoshida T, Murthy SN, Sakamuri SS, Katsuyama M, Clark RA, Delafontaine P, Chandrasekar B. Angiotensin II enhances AT(1)-Nox1 binding and stimulates arterial smooth muscle cell migration and proliferation through AT(1), Nox1, and interleukin18. Am J Physiol Heart Circ Physiol 303: H282-H296, 2012. First published May 25, 2012; doi:10.1152/ajpheart.00231.2012.-The redox- sensitive transcription factors NF-kappa B and activator protein-1 (AP-1) are critical mediators of ANG II signaling. The promitogenic and promigratory factor interleukin (IL)-18 is an NF-kappa B- and AP-1-responsive gene. Therefore, we investigated whether ANG II-mediated 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 (AT1) receptor. ANG II-induced superoxide generation, NF-kappa B 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-kappa B 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. AT1 physically associates with Nox1 in SMC, and ANG II enhanced this binding. Interestingly, exogenous IL-18 neither induced AT1 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 AT1 and was associated with increased AT(1)/Nox1 binding (despite lower AT1 levels); increased DPI-inhibitable superoxide production; increased phospho-IKK beta, 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.

• 出版日期2012-8