Arterial and Venous Endothelia Display Differential Functional Fractalkine (CX ₃ CL1) Expression by Angiotensin-II

Abstract

Objective-Angiotensin-II (Ang-II) promotes the interaction of mononuclear cells with arterioles and neutrophils with postcapillary venules. To investigate the mechanisms underlying this dissimilar response, the involvement of fractalkine (CX 3 CL1) was explored. Methods and Results-Enhanced CX 3 CL1 expression was detected in both cremasteric arterioles and postcapillary venules 24 hours after Ang-II intrascrotal injection. Arteriolar leukocyte adhesion was the unique parameter significantly reduced (83%) in animals lacking CX 3 CL1 receptor (CX 3 CR1). Human umbilical arterial and venous endothelial cell stimulation with 1 μmol/L Ang-II increased CX 3 CL1 expression, yet neutralization of CX 3 CL1 activity only significantly inhibited Ang-II-induced mononuclear cell-human umbilical arterial endothelial cell interactions (73%) but not with human umbilical venous endothelial cells. The use of small interfering RNA revealed the involvement of tumor necrosis factor-α in Ang-II-induced CX 3 CL1 upregulation and mononuclear cell arrest. Nox5 knockdown with small interfering RNA or pharmacological inhibition of extracellular signal-regulated kinases1/2, p38 mitogen-activated protein kinase, and nuclear factor-κB also abolished these responses. Finally, when human umbilical arterial endothelial cells were costimulated with Ang-II, tumor necrosis factor-α, and interferon-γ, CX 3 CL1 expression and mononuclear cell adhesiveness were more pronounced than when each stimulus was provided alone. Conclusion-These

Overexpression of ankyrin repeat domain 1 enhances cardiomyocyte apoptosis by promoting p53 activation and mitochondrial dysfunction in rodents

“…TNFα (tumour necrosis factor α), IL-1β (interleukin 1β) or TGFβ (transforming growth factor β) can upregulate Ankrd1 [32,33], whereas it is well known that AngII is able to induce the production of cytokines such as IL-1β and TNFα as well as up-regulation of TGFβ. Reports from our laboratory [17] and others [34] showed further that pressureoverload or AngII can increase the expression of the chemokine fractalkine; moreover, we confirmed that fractalkine significantly increases the expression of both IL-1β and TNFα [17]. These lines of evidence suggest that pro-apoptotic factors are able to upregulate Ankrd1 (Figure 9).…”

The Role of Chemokines in Hypertension

“…Increased ROS production results in decreased NO activity and thereby intensifies leukocyte migration and inflammation in the vascular wall. angiotensin II also stimulates the expression of CX3CR1, a fractalkine receptor in the arteries [46]. In vitro studies have shown that fractalkine is able to induce ROS, including superoxide ions, which results in reduced availability of NO and endothelial dysfunction [47].…”

Combined Sub-Optimal Doses of Rosuvastatin and Bexarotene Impair Angiotensin II-Induced Arterial Mononuclear Cell Adhesion Through Inhibition of Nox5 Signaling Pathways and Increased RXR/PPARα and RXR/PPARγ Interactions

“…Guided by our initial observations, and given that RhoA is acknowledged as a primary target of oxidative stress on Ang-II endothelial stimulation (43), we explored the effect of the RXR agonist and statin combination on NADPH-oxidasederived ROS production. Although Nox2, Nox4, and Nox5 are the most abundant NADPH oxidase isoforms in endothelial cells (29) and are induced by Ang-II (54), only Nox5 appears to play a major role in Ang-II-induced endothelial adhesiveness since both VCAM-1 and fractalkine upregulation and the subsequent MC arrest were found to be Nox5 mediated (39,54). We found that Ang-II-induced production of ROS was attenuated by preincubation of HUAECs with Rosu + Bex.…”

“…These agents initiate an Ang-II is implicated in atherogenesis (9), and we demonstrated that 4 h of exposure to Ang-II in vivo caused arteriolar leukocyte adhesion in the mesenteric microcirculation of the rat (2). Notably, mononuclear leukocyte recruitment by Ang-II was found to be mediated largely by tumor necrosis factor-a (TNFa) and the subsequent increased endothelial expression of fractalkine (CX 3 CL1) (37,54). Consequently, pharmacological modulation of inflammatory cell infiltration of the subendothelial space may impede the atherogenic process associated with different cardiovascular risk factors related to the renninangiotensin system.…”

“…Since Ang-II stimulation of endothelial cells can induce the production and release of different CXC and CC che-mokines, in addition to the expression of the membranebound chemokine fractalkine (36,42,54), we next evaluated the effect of Rosu + Bex on Ang-II-induced chemokine synthesis in human arterial endothelial cells. Significant increases in the levels of growth-regulated oncogene-a (GROa or CXCL1), interleukin-8 (IL-8 or CXCL8), monocyte chemotactic protein-1 (MCP-1 or CCL2), and regulated on activation, normal T cell expressed and secreted (RANTES or CCL5) were detected in the supernatant of HUAEC subjected to Ang-II stimulation for 4 h, as measured by enzyme-linked immunoassay (ELISA) ( Fig.…”