Aims Traffic noise may play an important role in the development and deterioration of ischemic heart disease. Thus, we sought to determine the mechanisms of cardiovascular dysfunction and inflammation induced by aircraft noise in a mouse model of myocardial infarction (MI) and in humans with incident MI. Methods and Results C57BL/6J mice were exposed to noise alone (average sound pressure level 72 dB; peak level 85 dB) up to 4d, resulting in pro-inflammatory aortic gene expression in the myeloid cell adhesion/diapedesis pathways. Noise alone promoted adhesion and infiltration of inflammatory myeloid cells in vascular/cardiac tissue, paralleled by an increased percentage of leukocytes with a pro-inflammatory, reactive oxygen species (ROS)-producing phenotype and augmented expression of Nox-2/phospho-NFκB in peripheral blood. Ligation of the LAD resulted in worsening of cardiac function, pronounced cardiac infiltration of CD11b+ myeloid cells and Ly6Chigh monocytes and induction of interleukin (IL) 6, IL-1β, CCL-2 and Nox-2, being aggravated by noise exposure prior to MI. MI induced stronger endothelial dysfunction and more pronounced increases in vascular ROS in animals preconditioned with noise. Participants of the population-based Gutenberg Health Cohort Study (median follow-up:11.4y) with incident MI revealed elevated CRP at baseline and worse LVEF after MI in case of a history of noise exposure and subsequent annoyance development. Conclusion Aircraft noise exposure before MI substantially amplifies subsequent cardiovascular inflammation and aggravates ischemic heart failure, facilitated by a pro-inflammatory vascular conditioning. Our translational results suggest, that measures to reduce environmental noise exposure will be helpful in improving clinical outcome of subjects with MI.

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Background: Psoriasis is a systemic inflammatory disorder, primarily characterized by skin plaques. It is linked to co-morbidities including cardiovascular disease and metabolic syndrome. Several studies demonstrate that dietary habits can influence psoriasis development and severity. However, the effect of different dietary protein levels on psoriasis development and severity is poorly understood. In this study, we examine the influence of dietary protein on psoriasis-like skin disease in mice. Methods: We fed male C57BL/6J mice with regular, low protein and high protein chow for 4 weeks. Afterwards, we induced psoriasis-like skin disease by topical imiquimod (IMQ)-treatment on ear and back skin. The local cutaneous and systemic inflammatory response was investigated using flow cytometry analysis, histology and quantitative rt-PCR. Results: After 5 days of IMQ-treatment, both diets reduced bodyweight in mice, whereas only the high protein diet slightly aggravated IMQ-induced skin inflammation. IMQ-treatment induced infiltration of myeloid cells, neutrophils, and monocytes/macrophages into skin and spleen independently of diet. After IMQ-treatment, circulating neutrophils and reactive oxygen species were increased in mice on low and high protein diets. Conclusion: Different dietary protein levels had no striking effect on IMQ-induced psoriasis but aggravated the systemic pro-inflammatory phenotype.

Psoriasis is an immune‐mediated inflammatory skin disease driven by interleukin‐17A (IL‐17A) and associated with cardiovascular dysfunction. We used a severe psoriasis mouse model of keratinocyte IL‐17A overexpression (K14‐IL‐17Aind/+, IL‐17Aind/+ control mice) to investigate the activity of neutrophils and a potential cellular interconnection between skin and vasculature. Levels of dermal reactive oxygen species (ROS) and their release by neutrophils were measured by lucigenin‐/luminol‐based assays, respectively. Quantitative RT‐PCR determined neutrophilic activity and inflammation‐related markers in skin and aorta. To track skin‐derived immune cells, we used PhAM‐K14‐IL‐17Aind/+ mice allowing us to mark all cells in the skin by photoconversion of a fluorescent protein to analyze their migration into spleen, aorta, and lymph nodes by flow cytometry. Compared to controls, K14‐IL‐17Aind/+ mice exhibited elevated ROS levels in the skin and a higher neutrophilic oxidative burst accompanied by the upregulation of several activation markers. In line with these results psoriatic mice displayed elevated expression of genes involved in neutrophil migration (e.g., Cxcl2 and S100a9) in skin and aorta. However, no direct immune cell migration from the psoriatic skin into the aortic vessel wall was observed. Neutrophils of psoriatic mice showed an activated phenotype, but no direct cellular migration from the skin to the vasculature was observed. This suggests that highly active vasculature‐invading neutrophils must originate directly from the bone marrow. Hence, the skin‐vasculature crosstalk in psoriasis is most likely based on the systemic effects of the autoimmune skin disease, emphasizing the importance of a systemic therapeutic approach for psoriasis patients.

Background Psoriasis is the most common chronic skin disease worldwide. Furthermore, it is an independent cardiovascular risk factor. Several genetic and inducible murine models reproduce specific aspects of the human disease. In mice genetically overexpressing IL-17A in keratinocytes or dendritic cells, we coulod show both aspects of the disease: cutaneous hallmarks and the vascular phenotype. The most popular inducible model consists of topical application of Imiquimod (IMQ), a Toll-like receptor 7/8 agonist. In this model, cardiovascular aspects have not been studied yet. Therefore, we examined vascular and hemodynamic effects in this most popular murine psoriasis model. Methods C57BL/6J mice were treated with 5% IMQ or sham cream. During treatment, we measured bodyweight, skin thickness and skin water loss. After 10 days, aortic relaxation studies were performed. For assessment of vascular inflammation, inflammatory cell infiltration into the aortic tissue was investigated by flow cytometric analysis. To record physical activity, blood pressure and heart rate, carotid catheters were implanted two weeks before treatment with IMQ. Blood pressure and heart rate were continuously recorded by receiver platforms. Results IMQ treatment resulted in severe skin inflammation and induced a skin barrier defect resulting in a 7-fold increase of transcutaneous water loss (from 11±6 ml/m2h to 77±30 ml/m2h). Physical activity decreased more than 50% after d1 of treatment and normalized at d7. Telemetric recording revealed a reflex tachycardia at 1d of IMQ-application (from 492±21 bpm to 524±20 bpm) followed by a significant reduction of heart rate for the next two days (456±18bpm). Systolic blood pressure showed a similar trend: after a fast increase (from 120±13 mmHg to 127±18 mmHg), blood pressure dropped below baseline at d2/3 with a subsequent recovery. We could display a highly significant positive correlation between blood pressure and heart rate during the treatment (R=0.6; p≤0.0001). Aortas from animals after 10d of IMQ-treatment showed an increased infiltration of CD45+ and CD11b+ inflammatory cells but no change of responsiveness to endothelium dependent and independent vasodilators in organ chamber studies. Conclusion Skin treatment with IMQ had severe implications on the hemodynamic system: After an initial peak of heart rate and blood pressure, mice showed significantly lower values for two days with a subsequent full recovery. Moreover, bodyweight and physical activity were significantly altered during treatment. Our data indicate that skin inflammation and inflammatory skin barrier disruption by IMQ forces a compensatory whole-body response. 10 days of IMQ-treatment resulted in vascular inflammation without mediating vascular dysfunction. In summary, we could reveal that IMQ-induced psoriasis, as the most popular murine psoriasis model worldwide, has extensive effects on the cardiovascular system. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Boehringer Ingelheim Foundation “Novel and neglected cardiovascular risk factors: molecular mechanisms and therapeutic implications”German Federal Ministry for Education and Research (BMBF EDU-V24)