The role of IL-6 in the physiologic versus hypertensive blood pressure actions of angiotensin II

Manhiani, Marlina; Seth, Dale M.; Banes-Berceli, Amy; Satou, Ryosuke; Navar, L. Gabriel; Brands, Michael

doi:10.14814/phy2.12595

Cited by 16 publications

(13 citation statements)

References 26 publications

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“…18 Investigations into the pathophysiology of hypertensive cardiovascular disease have identified a strong association with the proinflammatory cytokine IL-6, 19,20 and this peptide is likewise increased in plasma of patients with AAA. 11 The mechanism of IL-6 production in vascular inflammation has previously been linked to AngII, but this investigation has identified that tension alone can initiate VSMC production of IL-6.…”

Section: Discussionmentioning

confidence: 99%

Elevated Wall Tension Initiates Interleukin-6 Expression and Abdominal Aortic Dilation

Akerman

Stroud

Barrs

et al. 2018

Annals of Vascular Surgery

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Background Hypertension (HTN) has long been associated with abdominal aortic aneurysm (AAA) development, and these cardiovascular pathologies are biochemically characterized by elevated plasma levels of angiotensin II (AngII) as well as interleukin-6 (IL-6). A biologic relationship between HTN and AAA has not been established, however. Accordingly, the objective of this study was to evaluate whether elevated tension may initiate IL-6 production to accumulate monocyte/macrophages and promote dilation of the abdominal aorta (AA). Methods An IL-6 infusion model (4.36 µg/kg/day) was created utilizing an osmotic infusion pump, and after 4 weeks, AA diameter was measured by digital microscopy. The AA was then excised for CD68 immunostaining and flow cytometric analysis with CD11b and F4/80 to identify macrophages. Aortic segments from wild-type mice were suspended on parallel wires in an ex vivo tissue myograph at experimentally derived optimal tension (1.2 g) and in the presence of elevated tension (ET, 1.7 g) for 3 hr, and expression of IL-6 and monocyte chemoattractant protein-1 (MCP-1) was evaluated by quantitative polymerase chain reaction (QPCR). Isolated aortic vascular smooth muscle cells (VSMCs) were subjected to 12% biaxial cyclic stretch or held static (control) for 3 hr (n = 7), and IL-6 and MCP-1 expressions were evaluated by QPCR. Results Four-week IL-6 infusion resulted in an AA outer diameter that was 72.5 ± 5.6% (P < 0.05) greater than that of control mice, and aortic dilation was accompanied by an accumulation of macrophages in the AA medial layer as defined by an increase in CD68 + staining as well as an increase by flow cytometric quantification of CD11b+/F4/80+ cells. Wild-type AA segments did not respond to ex vivo application of ET but cyclic stretch of isolated VSMCs increased IL-6 (2.03 ± 0.3 fold) and MCP-1 (1.51 ± 0.11 fold) expression compared to static control (P < 0.05). Pretreatment with the selective STAT3 inhibitor WP1066 blunted the response in both cases. Interestingly, AngII did not stimulate expression of IL-6 and MCP-1 above that initiated by tension and again, the response was inhibited by WP1066, supporting an integral role of STAT3 in this pathway. Conclusions An IL-6 infusion model can initiate macrophage accumulation as well as aortic dilation, and under conditions of elevated tension, this proinflammatory cytokine can be produced by aortic VSMCs. By activation of STAT3, MCP-1 is expressed to increase media macrophage abundance and create an environment susceptible to dilation. This biomechanical association between HTN and aortic dilation may allow for the identification of novel therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Elevated Wall Tension Initiates Interleukin-6 Expression and Abdominal Aortic Dilation

Akerman

Stroud

Barrs

et al. 2018

Annals of Vascular Surgery

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“…At the other end of the spectrum, IL-6 -deficient mice have been used in a number of studies examining the effect of IL-6 -deficiency on both baseline blood pressure and on the development of hypertension [ 57 , 73 , 81 , 163 , 184 , 185 , 186 , 187 , 188 , 189 , 190 ]. Baseline blood pressure in IL-6 -deficient mice does not appear to be associated with alterations in arterial pressure, a consistent finding among several studies ( Table 2 ).…”

Section: Interleukin-6 and Blood Pressurementioning

confidence: 99%

Cellular and Oxidative Mechanisms Associated with Interleukin-6 Signaling in the Vasculature

Didion

2017

IJMS

156

102

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Reactive oxygen species, particularly superoxide, promote endothelial dysfunction and alterations in vascular structure. It is increasingly recognized that inflammatory cytokines, such as interleukin-6 (IL-6), contribute to endothelial dysfunction and vascular hypertrophy and fibrosis. IL-6 is increased in a number of cardiovascular diseases, including hypertension. IL-6 is also associated with a higher incidence of future cardiovascular events and all-cause mortality. Both immune and vascular cells produce IL-6 in response to a number of stimuli, such as angiotensin II. The vasculature is responsive to IL-6 produced from vascular and non-vascular sources via classical IL-6 signaling involving a membrane-bound IL-6 receptor (IL-6R) and membrane-bound gp130 via Jak/STAT as well as SHP2-dependent signaling pathways. IL-6 signaling is unique because it can also occur via a soluble IL-6 receptor (sIL-6R) which allows for IL-6 signaling in tissues that do not normally express IL-6R through a process referred to as IL-6 trans-signaling. IL-6 signaling mediates a vast array of effects in the vascular wall, including endothelial activation, vascular permeability, immune cell recruitment, endothelial dysfunction, as well as vascular hypertrophy and fibrosis. Many of the effects of IL-6 on vascular function and structure are representative of loss or reductions in nitric oxide (NO) bioavailability. IL-6 has direct effects on endothelial nitric oxide synthase activity and expression as well as increasing vascular superoxide, which rapidly inactivates NO thereby limiting NO bioavailability. The goal of this review is to highlight both the cellular and oxidative mechanisms associated with IL-6-signaling in the vascular wall in general, in hypertension, and in response to angiotensin II.

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“…Ang II has also been revealed to stimulate vascular smooth muscle cells to increase the synthesis and release of IL-6, andIL-6 upregulates Ang II receptors. Furthermore, during the pathogenesis of essential hypertension, Ang II has been demonstrated to increase peripheral resistance via smooth muscle contraction, and thus increase blood pressure (37).…”

Section: Discussionmentioning

confidence: 99%

Gardenia jasminoides has therapeutic effects on L-NNA-induced hypertension in vivo

Chen

Sun

et al. 2017

Molecular Medicine Reports

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Gardenia jasminoides is a plant that has been used in traditional Chinese medicine. It has four key active components (genipin gentiobioside, geniposide, crocin 1 and crocin 2). The aim of the present study was to determine the anti‑hypertension effects of Gardenia jasminoidesin vivo. The chemical composition of Gardenia jasminoides was determined using liquid chromatography. The anti‑hypertensive effects of Gardenia jasminoides were determined by a L‑NG‑nitroarginine (L‑NNA)‑induced hypertension animal model. Both Gardenia jasminoides plants of the Jiangjin County variety (CJGJ) and the Lichuan City variety (HLGJ) were used. HLGJ contained more geniposide than CJGJ. L‑NNA was used to induce hypertension in mice, and the mice were subsequently treated with CJGJ and HLGJ. The Gardenia jasminoides‑treated mice exhibited lower systolic (SBP), diastolic (DBP) and mean blood pressure (MBP) than the experimental control mice. Additionally, HLGL has a more potent effect on SBP, MBP and DBP than CJGJ. Following Gardenia jasminoides treatment, the nitric oxide contents in serum, heart, liver, kidney and stomach of mice were higher than the L‑NNA‑induced control mice, and the malondialdehyde contents were lower; the levels in HLGJ‑treated mice were closer to those normal mice than the levels in CJGJ‑treated mice were. Serum levels of endothelin‑1 and vascular endothelial growth factor were reduced by HLGJ treatment in hypertensive mice, whereas the calcitonin gene‑related peptide level was raised. Reverse transcription‑polymerase chain reaction analysis of mouse heart and vessel tissue demonstrated that HLGJ‑treated mice exhibited higher heme oxygenase‑1, neuronal nitric oxide synthase (nNOS), endothelial NOS, Bax, caspase‑3, caspase‑8, caspase‑9 mRNA expression levels and lower adrenomedullin, receptor activity modifying protein, interleukin‑1β, tumor necrosis factor‑α, inducible NOS, Bcl‑2, monocyte chemoattractant protein‑1, nuclear factor‑κB and matrix metalloproteinase‑2 and ‑9 mRNA expression compared with control hypertensive mice and CJGJ‑treated mice. In conclusion, Gardenia jasminoides has anti‑hypertensive effects, and these effects may be associated with the active component, geniposide.

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The role of IL-6 in the physiologic versus hypertensive blood pressure actions of angiotensin II

Cited by 16 publications

References 26 publications

Elevated Wall Tension Initiates Interleukin-6 Expression and Abdominal Aortic Dilation

Elevated Wall Tension Initiates Interleukin-6 Expression and Abdominal Aortic Dilation

Cellular and Oxidative Mechanisms Associated with Interleukin-6 Signaling in the Vasculature

Gardenia jasminoides has therapeutic effects on L-NNA-induced hypertension in vivo

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