Works in Progress
Project Number: 1R01HL133860-01 Contact PI / Project Leader: WANG, THOMAS J.
Title: TISSUE SODIUM, INFLAMMATION, AND BLOOD PRESSURE IN MESA
Awardee Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
- Abstract Text:
PROJECT SUMMARY/ABSTRACT Hypertension (HTN) is a major risk factor for cardiovascular, cerebrovascular, and renal disease, and its prevalence is increasing, particularly among the elderly. While the pathophysiology of HTN is multi-factorial, two major contributors appear to be salt-sensitivity and activation of the immune system. The prevailing paradigm regarding salt-sensitive HTN is based upon increased plasma volume and hydrostatic forces induced by intravascular sodium retention. Until recently, there was little consideration of the possibility that extravascular sodium stores may play a role in HTN. Through use of a novel non-invasive 23Na-magnetic resonance imaging (MRI) technique, we have demonstrated the presence of significant sodium accumulation in skin and skeletal muscle. Experimental evidence indicates that these tissue sodium stores can trigger the immune system, particularly the helper T cells (Th17) that produce interleukin-17 (IL17). Activation of these T cells and the cytokine they produce, IL17, induces HTN in animal models. In preliminary studies, we have shown that skin sodium content is associated with systolic blood pressure. We also found that circulating IL17 levels are higher in hypertensive compared with normotensive individuals. However, definitive data from larger, community cohorts are needed. The Multi-Ethnic Study of Atherosclerosis (MESA) is the ideal cohort in which to translate our preliminary findings. Our underlying hypothesis is that tissue sodium-induced inflammation contributes to the development and progression of HTN, particularly salt-sensitive HTN. We propose an ancillary study with the following specific aims: 1) to define the distribution of tissue Na+ content in middle-aged to elderly individuals in the community, 2) to investigate the association of tissue sodium levels with blood pressure, and 3) to examine the association of tissue sodium with Th17 and other cellular markers of inflammation. We will non-invasively quantify skin sodium concentration using 23Na-MRI and measure blood pressure in all eligible MESA participants at the Chicago, IL field center during exam 6 (2016-2018). We will also quantify the number and types of circulating immune cells, such as Th17 cells, among MESA participants who undergo MRI measurement of tissue sodium concentration. The proposed research represents a unique opportunity to leverage a large, well-phenotyped, community population in which to translate novel findings from preclinical and early human studies to gain a deeper understanding of pathophysiologic contributors to HTN. The proposed research represents a systematic effort to build upon the investigators' prior studies on the mechanisms underlying HTN and the novel interactions between tissue sodium, inflammation, and blood pressure. These studies have the potential to provide important insight into the determinants of HTN. Furthermore, because visualizing tissue sodium by MRI is a novel non-invasive technology, establishing that tissue sodium is associated with inflammation and HTN could suggest novel approaches to the prevention and treatment of HTN and related disorders.
Public Health Relevance Statement:
PROJECT NARRATIVE High blood pressure, or hypertension, is a major cause of heart disease, stroke, and kidney disease and is more common in middle-aged to elderly individuals. Salt (sodium) retention and inflammation are thought be important reasons why people develop hypertension, but the actual mechanisms are not completely understood. New data suggest that accumulation of sodium in tissues such as skin may be an important cause, by inducing inflammation; therefore, we propose to investigate this novel hypothesis by studying participants in the Multi-Ethnic Study of Atherosclerosis, which could lead to new approaches for treating hypertension.
Anti-interleukin 6 receptor antibodies attenuate antibody recall responses in a mouse model of allosensitization. 2014
Colorectal cancer progression is associated with accumulation of Th17 lymphocytes in tumor tissues and increased serum levels of interleukin-6. 2014
- In conclusion, the percentage of Th17 cells and the serum IL-6 level are significantly increased with aging, and their higher levels are correlated with colorectal cancer progression.
The Th17/Treg balance is disturbed during aging. 2013
Recent studies reported an increase of TH17 cells in aged humans and aged mice, but the role of TH17 cells and their relation to Tregs is poorly understood in human aging.
Potentiation of Th17 cytokines in aging process contributes to the development of colitis. 2012
However, the Th17 immune response in the aging process is still not clear.
Nuclear factor-kappaB-dependent reversal of aging-induced alterations in T cell cytokines. 2008 (Nuclear factor-kappaB )
Pharmacological correction of altered generation of Th17 cell cytokines in immunosenescence represents a novel therapeutic approach to aging-induced inflammatory diseases.
Hypothyroidism and Th17
open Question: the CoQ synthesis reduction in Hypot. increases Th17 number?
[Significance of the alteration of Th17 cells in patients with chronic lymphocytic thyroiditis]. 2009
CONCLUSION The frequencies of Th17 cell increased in patients with CLT which may suggest a potential role for Th17 in the progression and happen of CLT.
Vitamin A supplementation reduces the Th17-Treg - Related cytokines in obese and non-obese women. 2016
- OBJECTIVE The objective of the present study was to investigate the effect of vitamin A supplementation on serum Th17 (IL-6, IL-17, IFNγ) and Treg (TGF-β, IL-10) related cytokines in obese and non-obese women.
SUBJECTS AND METHODS In a randomized double blind placebo controlled design, 56 obese women were randomly assigned to receive either an oral dose of 25,000 IU retinyl palmitate or placebo per day for 4 months. Twenty eight ages matched non-obese women were also received vitamin A. At the study entry, anthropometric variables were measured and serum Th17 and Treg related cytokine profile were determined at baseline and 4 months after intervention.
RESULTS Significantly higher baseline concentrations of IL-6 were observed in obese compared with non-obese women (P < 0.05). However, the initial concentrations of other cytokines were not significantly different between groups. The mean concentrations of IL-17 and TGF-β were significantly decreased after vitamin A supplementation in non-obese and obese women respectively. Positive relationships between IL-17 and IL-10 (r = 0.42, P < 0.001), TGF-β and IL-17 (r = 0.35, P < 0.001) and between IL-10 and IFN-γ (r = 0.41, P = 0.002) in total participants were also observed.
CONCLUSIONS The results of the present study showed for the first time that vitamin A supplementation reduces serum concentrations of IL-17 and TGF-β in reproductive age women. Further studies are needed to explore the possible underlying mechanisms.
Adipocytes, like their progenitors, contribute to inflammation of adipose tissues through promotion of Th-17 cells and activation of monocytes, in obese subjects. 2016
- Metformin improves Treg/Th17 balance in CD4+ T cells in mice with high-fat diet-induced obesity.
Systemic and local interleukin-17 and linked cytokines associated with Sjögren's syndrome immunopathogenesis. 2009
- Transforming growth factor-β, IL-6 and IL-23, which are requisite promoters of Th17 differentiation, were found in abundance compared with the amounts in control tissues.