Angiotensin II Induces Interleukin-6 Transcription in Vascular Smooth Muscle Cells Through Pleiotropic Activation of Nuclear Factor-κB Transcription Factors

Abstract

—Interleukin-6 (IL-6) is a multifunctional cytokine expressed by angiotensin II (Ang II)-stimulated vascular smooth muscle cells (VSMCs) that functions as an autocrine growth factor. In this study, we analyze the mechanism for Ang II-inducible IL-6 expression in quiescent rat VSMCs. Stimulation with the Ang II agonist Sar 1 Ang II (100 nmol/L) induced transcriptional expression of IL-6 mRNA transcripts of 1.8 and 2.4 kb. In transient transfection assays of IL-6 promoter/luciferase reporter plasmids, Sar 1 Ang II treatment induced IL-6 transcription in a manner completely dependent on the nuclear factor-κB (NF-κB) motif. Sar 1 Ang II induced cytoplasmic-to-nuclear translocation of the NF-κB subunits Rel A and NF-κB1 with parallel changes in DNA-binding activity in a biphasic manner, which produced an early peak at 15 minutes followed by a nadir 1 to 6 hours later and a later peak at 24 hours. The early phase of NF-κB translocation was dependent on weak simultaneous proteolysis of the IκBα and β inhibitors, whereas later translocation was associated with enhanced processing of the p105 precursor into the mature 50-kDa NF-κB1 form. Pretreatment with a potent inhibitor of IκBα proteolysis, TPCK, completely blocked Sar 1 Ang IIAng II-induced NF-κB activation and induction of endogenous IL-6 gene expression, which indicated the essential role of NF-κB in mediating IL-6 expression. We conclude that Ang II is a pleiotropic regulator of the NF-κB transcription factor family and may be responsible for activating the expression of cytokine gene networks in VSMCs.

Polymorphism of 270 A > G in BRAP is Associated with Lower Ankle-Brachial Index in a Taiwanese Population

“…Our recent findings also show that BRAP can influence NF-B nucleus translocation, leading to an increase of proinflammatory molecules (unpublished data). In addition, previous studies [27][28][29][30][31][32][33] demonstrated that NF-B can regulate a number of inflammatory genes, including interleukin-6 (IL-6), tumor necrosis factor (TNF), vascular cellular adhesion molecule-1 (VCAM-1), E-selectin, inducible nitric oxide synthase (iNOS), matrix metallo-proteinases (MMPs) and CRP. BRAP was originally identified as a cytoplasmic protein that recognizes the nuclear localization signal of the breast cancer suppressor protein, BRCA-1 1,34) .…”

Comparison of Effects of Olmesartan and Telmisartan on Blood Pressure and Metabolic Parameters in Japanese Early-Stage Type-2 Diabetics with Hypertension

“…In agreement with these data, we also found that serum hs-CRP and IL-6 levels were significantly lower by olmesartan than by telmisartan treatment. Angiotensin II is known as one of the main effector peptides inducing IL-6 expression in vascular smooth muscle cells (30,31). In addition, it is well known that IL-6 induces CRP expression.…”

Angiotensin II induces IL-6 expression and the Jak-STAT3 pathway in aortic adventitia of LDL receptor-deficient mice

“…In addition to the well-studied VSMCs and macrophages, fibroblasts are also known to inducibly express IL-6 in response to inflammatory cytokines and/or AS [32][33][34][35][36]. Work from our group has shown that IL-6 is a highly inducible gene, a target for direct A-II activation through the ubiquitous NF-κB pathway [32].…”