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Monitoring Endothelin-A Receptor Expression during the Progression of Atherosclerosis.

ABSTRACT: Cardiovascular disease remains the most frequent cause of death worldwide. Atherosclerosis, an underlying cause of cardiovascular disease, is an inflammatory disorder associated with endothelial dysfunction. The endothelin system plays a crucial role in the pathogenesis of endothelial dysfunction and is involved in the development of atherosclerosis. We aimed to reveal the expression levels of the endothelin-A receptor (ET_AR) in the course of atherogenesis to reveal possible time frames for targeted imaging and interventions. We used the ApoE^-/- mice model and human specimens and evaluated ET_AR expression by quantitative rtPCR (qPCR), histology and fluorescence molecular imaging. We found a significant upregulation of ET_AR after 22 weeks of high-fat diet in the aortae of ApoE^-/- mice. With regard to translation to human disease, we applied the fluorescent probe to fresh explants of human carotid and femoral artery specimens. The findings were correlated with qPCR and histology. While ET_AR is upregulated during the progression of early atherosclerosis in the ApoE^-/- mouse model, we found that ET_AR expression is substantially reduced in advanced human atherosclerotic plaques. Moreover, those expression changes were clearly depicted by fluorescence imaging using our in-house designed ET_AR-Cy 5.5 probe confirming its specificity and potential use in future studies.

SUBMITTER: Stolting M

PROVIDER: S-EPMC7761144 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Monitoring Endothelin-A Receptor Expression during the Progression of Atherosclerosis.

Stölting Miriam M Geyer Christiane C Helfen Anne A Hahnenkamp Anke A Usai Marco V MV Wardelmann Eva E Kuhlmann Michael T MT Wildgruber Moritz M Höltke Carsten C

Biomedicines 20201126 12

Cardiovascular disease remains the most frequent cause of death worldwide. Atherosclerosis, an underlying cause of cardiovascular disease, is an inflammatory disorder associated with endothelial dysfunction. The endothelin system plays a crucial role in the pathogenesis of endothelial dysfunction and is involved in the development of atherosclerosis. We aimed to reveal the expression levels of the endothelin-A receptor (ET<sub>A</sub>R) in the course of atherogenesis to reveal possible time fram ...[more]

PMID: 33255872

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Project description:BackgroundEndothelin (ET-1) is one of the most potent vasoconstrictors and plays a seminal role in the pathogenesis of atherosclerosis. The present study was designed to test the hypothesis that long-term treatment with an endothelin-A (ET(A)) receptor antagonist improves coronary endothelial function in patients with early coronary atherosclerosis.Methods and resultsForty-seven patients with multiple cardiovascular risk factors, nonobstructive coronary artery disease, and coronary endothelial dysfunction were randomized in a double-blind manner to either the ET(A) receptor antagonist atrasentan (10 mg) or placebo for 6 months. Coronary endothelium-dependent vasodilation was examined by infusing acetylcholine (10(-6) to 10(-4) mol/L) in the left anterior descending coronary artery. N(G)-monomethyl-l-arginine was administered to a subgroup of patients. Endothelium-independent coronary flow reserve was examined by use of intracoronary adenosine and nitroglycerin. Baseline characteristics and incidence of adverse effects were similar between the 2 groups. There was a significant improvement in percent change of coronary blood flow in response to acetylcholine at 6 months from baseline in the atrasentan group compared with the placebo group (39.67%, 95% confidence interval 23.23% to 68.21%, versus -2.22%, 95% confidence interval -27.37% to 15.28%; P<0.001). No significant difference in the percent change of coronary artery diameter or change in coronary flow reserve was demonstrated. Coronary blood flow, coronary artery diameter, and the effect of N(G)-monomethyl-l-arginine were similar between the groups at baseline and at 6 months.ConclusionsThis study demonstrates that 6-month treatment with atrasentan improves coronary microvascular endothelial function and supports the role of the endogenous endothelin system in the regulation of endothelial function in early atherosclerosis in humans. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00271492.

Project description:Myelin-associated inhibitory factors within the central nervous system (CNS) are considered to be one of the main obstacles for axonal regeneration following disease or injury. The nogo receptor 1 (NgR1) has been well documented to play a key role in limiting axonal regrowth in the injured and diseased mammalian CNS. However, the role of nogo receptor in immune cell activation during CNS inflammation is yet to be mechanistically elucidated. Microglia/macrophages are immune cells that are regarded as pathogenic contributors to inflammatory demyelinating lesions in multiple sclerosis (MS). In this study, the animal model of MS, experimental autoimmune encephalomyelitis (EAE) was induced in ngr1+/+ and ngr1-/- female mice following injection with the myelin oligodendrocyte glycoprotein (MOG35-55) peptide. A fate-map analysis of microglia/macrophages was performed throughout spinal cord sections of EAE-induced mice at clinical scores of 0, 1, 2 and 3, respectively (increasing locomotor disability) from both genotypes, using the CD11b and Iba1 cell markers. Western immunoblotting using lysates from isolated spinal cord microglia/macrophages, along with immunohistochemistry and flow cytometric analysis, was performed to demonstrate the expression of nogo receptor and its two homologs during EAE progression. Myelin protein engulfment during EAE progression in ngr1+/+ and ngr1-/- mice was demonstrated by western immunblotting of lysates from isolated spinal cord microglia/macrophages, detecting levels of Nogo-A and MOG. The numbers of M1 and M2 microglia/macrophage phenotypes present in the spinal cords of EAE-induced ngr1+/+ and ngr1-/- mice, were assessed by flow cytometric analysis using CD38 and Erg-2 markers. A significant difference in microglia/macrophage numbers between ngr1+/+ and ngr1-/- mice was identified during the progression of the clinical symptoms of EAE, in the white versus gray matter regions of the spinal cord. This difference was unrelated to the expression of NgR on these macrophage/microglial cells. We have identified that as EAE progresses, the phagocytic activity of microglia/macrophages with myelin debris, in ngr1-/- mice, was enhanced. Moreover, we show a modulation from a predominant M1-pathogenic to the M2-neurotrophic cell phenotype in the ngr1-/- mice during EAE progression. These findings suggest that CNS-specific macrophages and microglia of ngr1-/- mice may exhibit an enhanced capacity to clear inhibitory molecules that are sequestered in inflammatory lesions.

Dataset Information

Monitoring Endothelin-A Receptor Expression during the Progression of Atherosclerosis.

Publications

Monitoring Endothelin-A Receptor Expression during the Progression of Atherosclerosis.

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