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Human monocyte transcriptional profiling identifies IL-18 receptor accessory protein and lactoferrin as novel immune targets in hypertension.
Alexander, MR, Norlander, AE, Elijovich, F, Atreya, RV, Gaye, A, Gnecco, JS, Laffer, CL, Galindo, CL, Madhur, MS
British journal of pharmacology. 2019;(12):2015-2027
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Abstract
BACKGROUND AND PURPOSE Monocytes play a critical role in hypertension. The purpose of our study was to use an unbiased approach to determine whether hypertensive individuals on conventional therapy exhibit an altered monocyte gene expression profile and to perform validation studies of selected genes to identify novel therapeutic targets for hypertension. EXPERIMENTAL APPROACH Next generation RNA sequencing identified differentially expressed genes in a small discovery cohort of normotensive and hypertensive individuals. Several of these genes were further investigated for association with hypertension in multiple validation cohorts using qRT-PCR, regression analysis, phenome-wide association study and case-control analysis of a missense polymorphism. KEY RESULTS We identified 60 genes that were significantly differentially expressed in hypertensive monocytes, many of which are related to IL-1β. Uni- and multivariate regression analyses of the expression of these genes with mean arterial pressure (MAP) revealed four genes that significantly correlated with MAP in normotensive and/or hypertensive individuals. Of these, lactoferrin (LTF), peptidoglycan recognition protein 1 and IL-18 receptor accessory protein (IL18RAP) remained significantly elevated in peripheral monocytes of hypertensive individuals in a separate validation cohort. Interestingly, IL18RAP expression associated with MAP in a cohort of African Americans. Furthermore, homozygosity for a missense single nucleotide polymorphism in LTF that decreases antimicrobial function and increases protein levels (rs1126478) was over-represented in patients with hypertension relative to controls (odds ratio 1.16). CONCLUSIONS AND IMPLICATIONS These data demonstrate that monocytes exhibit enhanced pro-inflammatory gene expression in hypertensive individuals and identify IL18RAP and LTF as potential novel mediators of human hypertension. LINKED ARTICLES This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.
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Effects of losartan treatment on T-cell activities and plasma leptin concentrations in primary hypertension.
Sonmez, A, Kisa, U, Uckaya, G, Eyileten, T, Comert, B, Koc, B, Kocabalkan, F, Ozata, M
Journal of the renin-angiotensin-aldosterone system : JRAAS. 2001;(2):112-6
Abstract
Recent evidence shows that leptin may contribute to elevated blood pressure (BP) and interact with the renin-angiotensin-aldosterone and cellular immune systems. Altered T-cell activities and changes in T-cell subset ratios have also been reported in hypertension. However, little is known about the effects of AT1-receptor antagonism on T-cell activities and plasma leptin concentrations in primary hypertension. We have, therefore, investigated the relationship between leptin and T-cell activities and the effect of an AT1-receptor antagonist, losartan, in primary hypertension. Twenty recently-diagnosed and untreated young adults (11 males and 9 females, age; 39.9+/-7.6 years, range 23-49 years, BMI; 27.6+/-3.7kg/m2) and 20 normotensive healthy, age-, sex- and BMI-matched controls were studied. The [3H]-thymidine uptakes of cultured lymphocytes were determined, both spontaneously and after stimulation with phytohaemagglutinin. The tests were performed before and after three months of treatment with losartan. The results indicate that the blastogenic responses of T-cells to phytohaemagglutinin are significantly higher in the patient group compared with controls (p=0.02). After normalisation of BP, T-cell responses were significantly reduced and were lower than in the controls (p=0.01). Pretreatment plasma leptin levels were significantly higher in hypertensives than in controls (p=0.01). However, losartan treatment had no significant effect on leptin concentrations; moreover, no correlation between leptin levels and T-cell activity was found. Our data show that plasma leptin levels and T-cell activity are markedly enhanced in untreated essential hypertension and that the alteration of T-cell activity is not related to plasma leptin levels. Antihypertensive treatment with losartan decreases T-cell activities but does not influence plasma leptin levels. We conclude that leptin levels are not affected by AT1-receptor blockade and are not related to T-cell activity.