Dokument: Effect of Short Chain Fatty Acids and Sodium Chloride on Immune Cell-mediated Cardiovascular Health

Titel:Effect of Short Chain Fatty Acids and Sodium Chloride on Immune Cell-mediated Cardiovascular Health
Weiterer Titel:Effekt von kurzkettigen Fettsäuren und Natriumchlorid auf die durch Immunzellen vermittelte kardiovaskuläre Gesundheit
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URN (NBN):urn:nbn:de:hbz:061-20211103-091046-6
Dokumententyp:Wissenschaftliche Abschlussarbeiten » Dissertation
Autor:M.Sc. Yakoub, Mina Gadelrab Botros [Autor]
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Dateien vom 28.10.2020 / geändert 28.10.2020
Beitragende:PD Dr. med. Stegbauer, Johannes [Gutachter]
Prof. Dr. rer. nat. Scheller, Jürgen [Gutachter]
Stichwörter:Cardiovascular health, Nutrition factors, Immune mediated effect.
Dewey Dezimal-Klassifikation:500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie
Beschreibung:Cardiovascular diseases such as atherosclerosis and aneurysm remain to be the leading cause of morbidity and mortality worldwide. The main risk factors for the development of atherosclerosis and aneurysm are hypertension and hyperlipidemia causing vascular injury. In this context, vascular injury is largely mediated by immune cells. Thus, either a hypertensive stimulus like angiotensin II (Ang II) or hyperlipidemia causes activation of proinflammatory T cells and macrophages infiltrating into the vasculature and the perivascular fat to cause endothelial dysfunction, inflammation, apoptosis, remodeling, extracellular matrix degeneration, and atherosclerotic plaque development. Nutrition factors have shown to influence the microbiome of the gut and thereby vascular diseases by modulating the immune response. Thus, the composition and production of bacterial metabolites resorbed and distributed in the circulation can affect the immune system and cardiovascular function. Here, we studied the immune-mediated effect of short chain fatty acids (SCFA) and salt, two important nutrition factors on vascular disease.
In part I, we investigated the effect of propionate (C3), one of the most important SCFAs, on Ang II-induced atherosclerosis. SCFA are produced by the gut microbiome as a result of fiber fermentation and have been shown to affect the immune response of the host. Here, we demonstrated that chronic C3 treatment has a pronounced anti-atherosclerotic effect in Ang II-infused (500ng/kg/min) ApoE-/- mice as it reduces significantly the development of atherosclerotic plaques in the aorta and the brachiocephalic artery compared to sham-treated mice. This effect was mainly immune-mediated. Immune cell infiltration into the vasculature was significantly reduced. Moreover, chronic C3 treatment shifted the immune response to an anti-inflammatory phenotype by reducing Th17 and CD4 effector memory cells and increasing CD4 naïve T-cells. Besides the immune-mediated effect, we showed that C3 improved endothelial dysfunction and reduced blood pressure. In addition, C3 attenuates Ang II-induced cardiac fibrosis and cardiac hypertrophy demonstrating an additional cardio-protective effect of C3.
In part II, we studied the effect of high salt intake on Ang II-induced abdominal aortic aneurysm (AAA). Chronic high salt intake is a major risk factor for cardiovascular diseases. Recent studies showed that excessive chronic salt intake affects the immune response. However, it remains unclear how salt accelerates vascular damage via an immune cell-mediated mechanism. To answer this question, we pre-treated ApoE-/- mice with high salt (1% salt via drinking water) for two weeks. One week after switching to normal salt intake, AAA was induced by chronic Ang II infusion (1000ng/kg/min). AAA and aortic inflammation were assessed by a newly established magnetic resonance imaging (MRI) protocol. Compared to sham pre-treated mice, salt pre-treatment increased the incidence of AAA and worsened the outcome in ApoE-/- mice. This detrimental outcome was accompanied by accelerated vascular inflammation detected in vivo by MRI in salt-pre-treated mice. Further analysis revealed that cytokines characterizing a T-cell or macrophage dependent immune response were significantly increased in aortas of salt pre-treated mice. Beside an aggravated increase in effector and central memory CD4 T-cells, salt pre-treatment induced an increase in the pro-inflammatory CD8 T-cell subsets in the aorta and spleen. The effect of salt on CD8 differentiation was confirmed by in vitro experiments. Our study highlights the role of CD8 T-cells on the salt-mediated vascular injury. In addition, frequencies of neutrophils and neutrophil elastase expression was significantly increased in aortas of salt pre-treated ApoE-/- mice suggesting a direct effect of salt pre-treatment on neutrophil function and thereby on AAA formation. Notably, pro-inflammatory M1 macrophages seem to be more abundant in the salt pre-treated mice. Here, we showed that salt exacerbates AAA via an immune cell-mediated mechanism. T-cells, neutrophils, and macrophages were demonstrated to be the key players in the salt-mediated vascular injury.
In this study, we demonstrated that C3 and salt modulated the immune response in the Ang II-infused ApoE-/- mice differently and in turn affected the vascular injury. C3 and other SCFAs are produced as a result of fiber intake. Fibers and salt are main nutrition components. Changing food habits such as increased fiber intake and reduced salt intake will decrease significantly the cardiovascular disease within the populations.
Lizenz:In Copyright
Fachbereich / Einrichtung:Mathematisch- Naturwissenschaftliche Fakultät
Dokument erstellt am:03.11.2021
Dateien geändert am:03.11.2021
Promotionsantrag am:07.07.2020
Datum der Promotion:24.09.2020
Status: Gast