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BACKGROUND: Dietary high salt (HS) intake has a strong impact on cardiovascular diseases. Here, we investigated the link between HS-aggravated immune responses and the development of hypertensive vascular disease. METHODS: ApolipoproteinE-deficient mice were transiently treated with HS (1% NaCl) via drinking water for 2 weeks, followed by a washout period, and subsequent Ang II (angiotensin II) infusion (1000 ng/kg per min for 10 days) to induce abdominal aortic aneurysms/dissections and inflammation. RESULTS: While transient HS intake alone triggered nonpathologic infiltration of activated T cells into the aorta, subsequent Ang II infusion increased mortality and the incidence of abdominal aortic aneurysms/dissections and atherosclerosis compared with hypertensive control mice. There were no differences in blood pressure between both groups. In transient HS-treated hypertensive mice, the aortic injury was associated with increased inflammation, accumulation of neutrophils, monocytes, CD69+CD4+ T cells, as well as CD4+ and CD8+ memory T cells. Mechanistically, transient HS intake increased expression levels of aortic RORγt as well as splenic CD4+TH17 and CD8+TC1 T cells in Ang II–treated mice. Isolated aortas of untreated mice were incubated with supernatants of TH17, TH1, or TC1 cells polarized in vitro under HS or normal conditions which revealed that secreted factors of HS-differentiated TH17 and TC1 cells, but not TH1 cells accelerated endothelial dysfunction. CONCLUSIONS: Our data suggest that transient HS intake induces a subclinical T-cell–mediated aortic immune response, which is enhanced by Ang II. We propose a 2-hit model, in which HS acts as a predisposing factor to enhance hypertension-induced TH17 and TC1 polarization and aortic disease. [ABSTRACT FROM AUTHOR]

Background: Ciliary neurotrophic factor (CNTF), mainly known for its neuroprotective properties, belongs to the IL-6 (interleukin-6) cytokine family. In contrast to IL-6, the effects of CNTF on the vasculature have not been explored. Here, we examined the role of CNTF in AngII (angiotensin II)-induced hypertension., Methods: Hypertension was chronically induced with AngII (1000 ng/kg per minute, osmotic mini-pumps, 14 days) in CNTF-knockout and wild-type mice (with or without nephrectomy and 1% NaCl drinking water). Blood pressure was measured by tail-cuff and radiotelemetry. Effects of CNTF on vascular function and the JAK2/STAT3 pathway were measured in vivo, in the isolated perfused kidney, and in mouse and human vascular smooth muscle cells., Results: At baseline, systolic blood pressure was similar between both groups. During AngII infusion, blood pressure increase was significantly attenuated and hypertensive heart and kidney damage was significantly attenuated in CNTF-knockout compared with wild-type mice. Accordingly, renal pressor response to AngII but not KCl or phenylephrine was significantly decreased in CNTF-knockout compared with wild-type mice. Acute CNTF (5 µmol/L) administration nearly restored the AngII-dependent renal pressor response. Chronic CNTF treatment in CNTF-knockout mice increased blood pressure response to AngII to levels observed in wild-type mice. CNTF augments AngII-induced activation of the JAK2/STAT3 pathway in vitro in vascular smooth muscle cells. The significance of this interaction was shown, as the increase in renal pressor response by CNTF was abolished by JAK2/STAT3 inhibitors., Conclusions: Our results demonstrate a major impact of CNTF on blood pressure regulation by modulating AngII-induced pressor response via a JAK2/STAT3-dependent mechanism and indicate that CNTF is an important regulatory cytokine in hypertension.