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      Chemerin inhibits vascular calcification through ChemR23 and is associated with lower coronary calcium in chronic kidney disease

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          Abstract

          Background

          Chemerin is an adipokine that signals through the G protein‐coupled receptor ChemR23 and is associated with inflammation, glucose homeostasis, lipid metabolism and renal function, all of which strongly influence cardiovascular risk. However, elevated chemerin provides a survival advantage in patients with chronic kidney disease ( CKD), but how this relates to the cardiovascular phenotype is unknown.

          Objectives

          The aim of the present study was to establish the association of chemerin with coronary calcification and to determine the effects of chemerin signalling, through ChemR23, in vascular smooth muscle cell ( VSMC) calcification.

          Methods

          Plasma chemerin was measured in 113 patients with CKD and 50 healthy controls. All patients underwent computed tomography to determine coronary artery calcium ( CAC) score. VSMCs were isolated from wild‐type and ChemR23 knock‐out mice and treated with chemerin.

          Results

          Multivariate analyses established creatinine, cholesterol, body mass index and tumour necrosis factor as significant confounders for circulating chemerin levels. Despite these positive associations with renal function, cardiometabolic risk factors and inflammation, chemerin was inversely associated with CAC both in an age‐ and sex‐adjusted analysis and in a multivariate analysis adjusting for the aforementioned confounders. In addition, circulating chemerin levels were associated with the calcification inhibitors matrix gla protein ( MGP) and fetuin‐A. Finally, chemerin significantly reduced phosphate‐induced calcification and increased MGP expression in VSMCs, whereas chemerin was devoid of these effects in VSMCs lacking ChemR23.

          Conclusion

          In conclusion, these results suggest that chemerin signalling through ChemR23 in VSMCs protects against vascular calcification in CKD.

          Abstract

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          Most cited references28

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          The influence of heart rate on augmentation index and central arterial pressure in humans.

          Arterial stiffness is an important determinant of cardiovascular risk. Augmentation index (AIx) is a measure of systemic arterial stiffness derived from the ascending aortic pressure waveform. The aim of the present study was to assess the effect of heart rate on AIx. We elected to use cardiac pacing rather than chronotropic drugs to minimize confounding effects on the systemic circulation and myocardial contractility. Twenty-two subjects (13 male) with a mean age of 63 years and permanent cardiac pacemakers in situ were studied. Pulse wave analysis was used to determine central arterial pressure waveforms, non-invasively, during incremental pacing (from 60 to 110 beats min-1), from which AIx and central blood pressure were calculated. Peripheral blood pressure was recorded non-invasively from the brachial artery. There was a significant, inverse, linear relationship between AIx and heart rate (r = -0.76; P < 0.001). For a 10 beats min-1 increment, AIx fell by around 4 %. Ejection duration and heart rate were also inversely related (r = -0. 51; P < 0.001). Peripheral systolic, diastolic and mean arterial pressure increased significantly during incremental pacing. Although central diastolic pressure increased significantly with pacing, central systolic pressure did not. There was a significant increase in the ratio of peripheral to central pulse pressure (P < 0.001), which was accounted for by the observed change in central pressure augmentation. These results demonstrate an inverse, linear relationship between AIx and heart rate. This is likely to be due to alterations in the timing of the reflected pressure wave, produced by changes in the absolute duration of systole. Consideration of wave reflection and aortic pressure augmentation may explain the lack of rise in central systolic pressure during incremental pacing despite an increase in peripheral pressure.
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            Influence of age, risk factors, and cardiovascular and renal disease on arterial stiffness: clinical applications.

            Age is the main clinical determinant of large artery stiffness. Central arteries stiffen progressively with age, whereas peripheral muscular arteries change little with age. A number of clinical studies have analyzed the effects of age on aortic stiffness. Increase of central artery stiffness with age is responsible for earlier wave reflections and changes in pressure wave contours. The stiffening of aorta and other central arteries is a potential risk factor for increased cardiovascular morbidity and mortality. Arterial stiffening with aging is accompanied by an elevation in systolic blood pressure (BP) and pulse pressure (PP). Although arterial stiffening with age is a common situation, it has now been confirmed that older subjects with increased arterial stiffness and elevated PP have higher cardiovascular morbidity and mortality. Increase in aortic stiffness with age occurs gradually and continuously, similarly for men and women. Cross-sectional studies have shown that aortic and carotid stiffness (evaluated by the pulse wave velocity) increase with age by approximately 10% to 15% during a period of 10 years. Women always have 5% to 10% lower stiffness than men of the same age. Although large artery stiffness increases with age independently of the presence of cardiovascular risk factors or other associated conditions, the extent of this increase may depend on several environmental or genetic factors. Hypertension may increase arterial stiffness, especially in older subjects. Among other cardiovascular risk factors, diabetes type 1 and 2 accelerates arterial stiffness, whereas the role of dyslipidemia and tobacco smoking is unclear. Arterial stiffness is also present in several cardiovascular and renal diseases. Patients with heart failure, end stage renal disease, and those with atherosclerotic lesions often develop central artery stiffness. Decreased carotid distensibility, increased arterial thickness, and presence of calcifications and plaques often coexist in the same subject. However, relationships between these three alterations of the arterial wall remain to be explored.
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              Chemerin correlates with markers for fatty liver in morbidly obese patients and strongly decreases after weight loss induced by bariatric surgery.

              Chemerin is a new adipokine involved in in vitro adipogenesis and insulin resistance and associates with body mass index (BMI) in vivo. We investigated the role of chemerin in morbid obesity, associated metabolic diseases (insulin resistance, hepatic diseases), and postsurgery-induced weight loss. This was a prospective study performed at a university hospital. Subjects included 60 obese female patients (BMI 50.0 +/- 1.0 kg/m(-2)) being candidates for gastric bypass. Patients were examined before and 3, 6, and 12 months after surgery. In 27 patients, chemerin was measured after 2 yr. Outcomes included chemerin, anthropometric parameters, homeostasis model assessment for insulin resistance index (HOMA-IR), cholesterol, high-density lipoprotein, triglycerides, C-reactive protein, adipokines at all time points; and liver histology and macrophage content in fat at baseline. Chemerin was substantially elevated in obese patients compared with nonobese persons (353.8 +/- 18.0 vs. 191 +/- 14 ng/ml, P < 0.001). Preoperatively, chemerin concentrations correlated positively with BMI, C-reactive protein, IL-6, HOMA-IR, and the amount of omental macrophages and negatively with high-density lipoprotein levels. Baseline chemerin was elevated in patients with a significant activity score for nonalcoholic fatty liver disease, portal inflammation, fibrosis, and fibroinflammation. After surgery, chemerin decreased significantly to 253.0 +/- 14.9 ng/ml after 1 yr and pursued its decrease in patients studied for 2 yr. After surgery, chemerin concentrations positively correlated with triglycerides. The strong decrease of chemerin in the 3 months after surgery was associated with the decrease in HOMA-IR and blood glucose. Chemerin concentrations are elevated in morbidly obese patients and correlated with insulin resistance and markers of liver pathology. Chemerin plasma concentrations decreased after bariatric surgery. This study suggests that chemerin might mediate metabolic alterations in obesity, drastically improving after gastric bypass.
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                Author and article information

                Contributors
                peter.stenvinkel@ki.se
                Journal
                J Intern Med
                J. Intern. Med
                10.1111/(ISSN)1365-2796
                JOIM
                Journal of Internal Medicine
                John Wiley and Sons Inc. (Hoboken )
                0954-6820
                1365-2796
                07 July 2019
                October 2019
                : 286
                : 4 ( doiID: 10.1111/joim.v286.4 )
                : 449-457
                Affiliations
                [ 1 ] Department of Medicine Solna Karolinska Institutet Stockholm Sweden
                [ 2 ] Division of Renal Medicine Department of Clinical Science, Intervention and Technology Karolinska Institutet, Campus Flemingsberg Stockholm Sweden
                [ 3 ] Division of Medical Imaging and Technology Department of Clinical Science, Intervention and Technology Karolinska Institutet, Campus Flemingsberg Stockholm Sweden
                [ 4 ] Theme Heart and Vessels Division of Valvular and Coronary Disease Karolinska University Hospital Stockholm Sweden
                Author notes
                [*] [* ] Correspondence: Peter Stenvinkel MD, PhD, Renal Medicine and Baxter Novum, Hälsovägen 7C (Neo, elevator M1 floor 8), 141 57 Huddinge, Sweden.

                (fax: +46‐8‐58583982; e‐mail: peter.stenvinkel@ 123456ki.se ).

                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-0536-5327
                https://orcid.org/0000-0003-0853-5141
                Article
                JOIM12940
                10.1111/joim.12940
                6852438
                31197872
                825c9257-5110-436e-8547-4bb75d5505bd
                © 2019 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Page count
                Figures: 4, Tables: 1, Pages: 9, Words: 5016
                Funding
                Funded by: Westmans Foundation
                Funded by: Swedish Research Council , open-funder-registry 10.13039/501100001862;
                Funded by: Swedish Heart and Lung Foundation
                Funded by: Njurfonden , open-funder-registry 10.13039/501100008035;
                Funded by: Konung Gustaf V:s och Drottning Victorias Frimurarstiftelse (MB)
                Funded by: Stockholm County Council (PS, MB)
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                October 2019
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.1 mode:remove_FC converted:13.11.2019

                Internal medicine
                adipokines,arterial stiffness,biomarkers,coronary artery disease,inflammation
                Internal medicine
                adipokines, arterial stiffness, biomarkers, coronary artery disease, inflammation

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