Angiotensin II enhances AT₁-Nox1 binding and stimulates arterial smooth muscle cell migration and proliferation through AT₁, Nox1, and interleukin-18

Abstract

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-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 (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-IKKβ, 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.

Naringenin Inhibits Angiotensin II-Induced Vascular Smooth Muscle Cells Proliferation and Migration and Decreases Neointimal Hyperplasia in Balloon Injured Rat Carotid Arteries through Suppressing Oxidative Stress

“…25,35) Also, angiotensin II can induce NADPH oxidase 1 expression and increase ROS production in VSMCs. [36][37][38] In this study, we found that naringenin could significantly decrease the level of ROS production in angiotensin II-treated VSMCs in vitro and the serum level of 8-iso-PGF2α, an oxidative stress marker, in balloon injured rats. Since NADPH oxidase and SOD are important enzymes in regulation of ROS production and degradation, respectively, 39,40) we further investigated whether naringenin could change the activities of NADPH oxidase and SOD.…”

Genetic Targeting or Pharmacologic Inhibition of NADPH Oxidase Nox4 Provides Renoprotection in Long-Term Diabetic Nephropathy

“…46,47 Angiotensin II induces upregulation of Nox1. 48 Therefore, it has been postulated that Nox1 could play an important role in the development and progression of diabetic nephropathy. 44,45 However, in our study, Nox1 deletion was not associated with an improvement in diabetes-related renal injury.…”

NADPH Oxidase 1 Plays a Key Role in Diabetes Mellitus–Accelerated Atherosclerosis

“…45 In the balloon injury model in rats a recent report has described a role for Nox1 involving the direct binding of this enzyme to the AT1 receptor. 46 In STZ-diabetes mellitus, activation of Nox1 but not Nox4 or Nox2 has been implicated in eNOS uncoupling and endothelial dysfunction, although these studies were performed in a nonatherosclerosis prone mouse model. 44 The role of Nox1 in atherosclerosis has not been extensively explored.…”