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- Caravaca, A. S., et al.
(author)
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Vagus nerve stimulation promotes resolution of inflammation by a mechanism that involves Alox15 and requires the α7nAChR subunit
- 2022
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:22
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Journal article (peer-reviewed)abstract
- Nonresolving inflammation underlies a range of chronic inflammatory diseases, and therapeutic acceleration of resolution of inflammation may improve outcomes. Neural reflexes regulate the intensity of inflammation (for example, through signals in the vagus nerve), but whether activation of the vagus nerve promotes the resolution of inflammation in vivo has been unknown. To investigate this, mice were subjected to electrical vagus nerve stimulation (VNS) or sham surgery at the cervical level followed by zymosan-induced peritonitis. The duration of inflammation resolution was significantly reduced and efferocytosis was significantly increased in mice treated with VNS as compared with sham. Lipid mediator (LM) metabololipidomics revealed that mice treated with VNS had higher levels of specialized proresolving mediators (SPMs), particularly from the omega-3 docosahexaenoic (DHA) and docosapentaenoic (n-3 DPA) metabolomes, in peritoneal exudates. VNS also shifted the ratio between proinflammatory and proresolving LMs toward a proresolving profile, but this effect by VNS was inverted in mice deficient in 12/15-lipoxgenase (Alox15), a key enzyme in this SPM biosynthesis. The significant VNS-mediated reduction of neutrophil numbers in peritoneal exudates was absent in mice deficient in the cholinergic α7-nicotinic acetylcholine receptor subunit (α7nAChR), an essential component of the inflammatory reflex. Thus, VNS increased local levels of SPM and accelerated resolution of inflammation in zymosan-induced peritonitis by a mechanism that involves Alox15 and requires the α7nAChR.
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- Gallina, AL, et al.
(author)
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AMPA-Type Glutamate Receptors Associated With Vascular Smooth Muscle Cell Subpopulations in Atherosclerosis and Vascular Injury
- 2021
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In: Frontiers in cardiovascular medicine. - : Frontiers Media SA. - 2297-055X. ; 8, s. 655869-
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Journal article (peer-reviewed)abstract
- Objectives and Aims: Vascular smooth muscle cells (VSMCs) are key constituents of both normal arteries and atherosclerotic plaques. They have an ability to adapt to changes in the local environment by undergoing phenotypic modulation. An improved understanding of the mechanisms that regulate VSMC phenotypic changes may provide insights that suggest new therapeutic targets in treatment of cardiovascular disease (CVD). The amino-acid glutamate has been associated with CVD risk and VSMCs metabolism in experimental models, and glutamate receptors regulate VSMC biology and promote pulmonary vascular remodeling. However, glutamate-signaling in human atherosclerosis has not been explored.Methods and Results: We identified glutamate receptors and glutamate metabolism-related enzymes in VSMCs from human atherosclerotic lesions, as determined by single cell RNA sequencing and microarray analysis. Expression of the receptor subunits glutamate receptor, ionotropic, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA)-type subunit 1 (GRIA1) and 2 (GRIA2) was restricted to cells of mesenchymal origin, primarily VSMCs, as confirmed by immunostaining. In a rat model of arterial injury and repair, changes of GRIA1 and GRIA2 mRNA level were most pronounced at time points associated with VSMC proliferation, migration, and phenotypic modulation. In vitro, human carotid artery SMCs expressed GRIA1, and selective AMPA-type receptor blocking inhibited expression of typical contractile markers and promoted pathways associated with VSMC phenotypic modulation. In our biobank of human carotid endarterectomies, low expression of AMPA-type receptor subunits was associated with higher content of inflammatory cells and a higher frequency of adverse clinical events such as stroke.Conclusion: AMPA-type glutamate receptors are expressed in VSMCs and are associated with phenotypic modulation. Patients suffering from adverse clinical events showed significantly lower mRNA level of GRIA1 and GRIA2 in their atherosclerotic lesions compared to asymptomatic patients. These results warrant further mapping of neurotransmitter signaling in the pathogenesis of human atherosclerosis.
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- Ahmed, M., et al.
(author)
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Molecular Imaging of Inflammation in a Mouse Model of Atherosclerosis Using a Zirconium-89-Labeled Probe
- 2020
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In: International Journal of Nanomedicine. - 1178-2013. ; 15, s. 6137-6152
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Journal article (peer-reviewed)abstract
- Background: Beyond clinical atherosclerosis imaging of vessel stenosis and plaque morphology, early detection of inflamed atherosclerotic lesions by molecular imaging could improve risk assessment and clinical management in high-risk patients. To identify inflamed atherosclerotic lesions by molecular imaging in vivo, we studied the specificity of our radiotracer based on maleylated (Mal) human serum albumin (HSA), which targets key features of unstable atherosclerotic lesions. Materials and Methods: Mal-HSA was radiolabeled with a positron-emitting metal ion, zirconium-89 (Zr-89(4+)). The targeting potential of this probe was compared with unspecific Zr-89-HSA and F-18-FDG in an experimental model of atherosclerosis (Apoe(-/-) mice, n=22), and compared with wild-type (WT) mice (C57BL/6J, n=21) as controls. Results: PET/MRI, gamma counter measurements, and autoradiography showed the accumulation of Zr-89-Mal-HSA in the atherosclerotic lesions of Apoe(-/-) mice. The maximum standardized uptake values (SUVmax) for Zr-89-Mal-HSA at 16 and 20 weeks were 26% and 20% higher (P<0.05) in Apoe(-/-) mice than in control WT mice, whereas no difference in SUVmax was observed for F-18-FDG in the same animals. Zr-89-Mal-HSA uptake in the aorta, as evaluated by a gamma counter 48 h postinjection, was 32% higher (P<0.01) for Apoe(-/-) mice than in WT mice, and the aorta-to-blood ratio was 8-fold higher (P<0.001) for Zr-89-Mal-HSA compared with unspecific Zr-89-HSA. HSA-based probes were mainly distributed to the liver, spleen, kidneys, bone, and lymph nodes. The phosphor imaging autoradiography (PI-ARG) results corroborated the PET and gamma counter measurements, showing higher accumulation of Zr-89-Mal-HSA in the aortas of Apoe(-/-) mice than in WT mice (9.4 +/- 1.4 vs 0.8 +/- 0.3%; P<0.001). Conclusion: Zr-89 radiolabeling of Mal-HSA probes resulted in detectable activity in atherosclerotic lesions in aortas of Apoe(-/-) mice, as demonstrated by quantitative in vivo PET/MRI. Zr-89-Mal-HSA appears to be a promising diagnostic tool for the early identification of macrophage-rich areas of inflammation in atherosclerosis.
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- Caravaca, AS, et al.
(author)
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Neural reflex control of vascular inflammation
- 2020
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In: Bioelectronic medicine. - : Springer Science and Business Media LLC. - 2332-8886. ; 6, s. 3-
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Journal article (peer-reviewed)abstract
- Atherosclerosis is a multifactorial chronic inflammatory disease that underlies myocardial infarction and stroke. Efficacious treatment for hyperlipidemia and hypertension has significantly reduced morbidity and mortality in cardiovascular disease. However, atherosclerosis still confers a considerable risk of adverse cardiovascular events. In the current mechanistic understanding of the pathogenesis of atherosclerosis, inflammation is pivotal both in disease development and progression. Recent clinical data provided support for this notion and treatment targeting inflammation is currently being explored. Interestingly, neural reflexes regulate cytokine production and inflammation. Hence, new technology utilizing implantable devices to deliver electrical impulses to activate neural circuits are currently being investigated in treatment of inflammation. Hopefully, it may become possible to target vascular inflammation in cardiovascular disease using bioelectronic medicine. In this review, we discuss neural control of inflammation and the potential implications of new therapeutic strategies to treat cardiovascular disease.
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