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      Diabetes-induced early molecular and functional changes in aortic heart valves in a murine model of atherosclerosis

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          Abstract

          Diabetes contributes directly to the development of cardiovascular aortic valve disease. There is currently no drug therapy available for a dysfunctional valve and this urges the need for additional research to identify distinctive mechanisms of cardiovascular aortic valve disease evolution. The aim of this study was to evaluate changes of valvular aortic lesions induced in a hyperlipemic ApoE −/− mouse model by early type 1 diabetes onset (at 4 and 7 days after streptozotocin induction). The haemodynamic valve parameters were evaluated by echography and blood samples and aortic valves were collected. Plasma parameters were measured, and inflammatory, remodelling and osteogenic markers were evaluated in the aortic valves. Next, correlations between all parameters were determined. The results showed early aortic valve dysfunction detected by echography after 1 week of diabetes; lesions were found in the aortic root. Moreover, increased expression of cell adhesion molecules, extracellular matrix remodelling and osteogenic markers were detected in hyperlipemic ApoE −/− diabetic mice. Significant correlations were found between tissue valve biomarkers and plasmatic and haemodynamic parameters. Our study may help to understand the mechanisms of aortic valve disease in the diabetic milieu in order to discover and validate new biomarkers of cardiovascular aortic valve disease in diabetes and reveal new possible targets for nanobiotherapies.

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          Most cited references27

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          Calcification in Aortic Stenosis: The Skeleton Key.

          Aortic stenosis is a common, potentially fatal condition that is set to become an increasing public health burden. Once symptoms develop, there is an inexorable deterioration with a poor prognosis. Despite this, there are no medical therapies capable of modifying disease progression, and the only available treatment is aortic valve replacement, to which not all patients are suited. Conventional teaching suggests that aortic stenosis is a degenerative condition whereby "wear and tear" leads to calcium deposition within the valve. Although mechanical stress and injury are important factors, it is becoming increasingly appreciated that aortic stenosis is instead governed by a highly complex, regulated pathological process with similarities to skeletal bone formation. This review discusses the pathophysiology of aortic stenosis with an emphasis on the emerging importance of calcification, how this can be visualized and monitored using noninvasive imaging, and how our improved knowledge may ultimately translate into novel disease-modifying treatments.
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            Plasma Fetuin-A Levels and the Risk of Type 2 Diabetes

            OBJECTIVE—The liver-secreted protein fetuin-A induces insulin resistance in animals, and circulating fetuin-A is elevated in insulin resistance and fatty liver in humans. We investigated whether plasma fetuin-A levels predict the incidence of type 2 diabetes in a large prospective, population-based study. RESEARCH DESIGN AND METHODS—A case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study comprising 27,548 subjects was designed. We randomly selected a subcohort of 2,500 individuals of whom 2,164 were diabetes free at baseline and had anamnestic, anthropometrical, and metabolic data for analysis. Of the 849 incident diabetic case subjects identified in the full cohort during 7 years of follow-up, 703 remained for analyses after similar exclusions. RESULTS—Plasma fetuin-A levels were positively associated with diabetes risk after adjustment for age (relative risk [RR] for extreme quintiles 1.75 [95% CI 1.32–2.31]; RR for 10 μg/ml 1.04 [1.03–1.06]). The association remained significant after adjustment for sex, BMI, waist circumference, and lifestyle risk factors (RR for 10 μg/ml 1.03 [1.01–1.06]). Adjustment for glucose, triglycerides, HDL cholesterol, A1C, γ-glutamyltransferase, or high-sensitivity C-reactive protein or mutual adjustment for these biomarkers did not appreciably change this result (RR for 10 μg/ml full adjusted model 1.05 [1.02–1.07]). Furthermore, fetuin-A was associated with increased diabetes risk particularly in individuals with elevated plasma glucose. CONCLUSIONS—Our data suggest that fetuin-A is an independent risk factor of type 2 diabetes.
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              Fetuin-A: a multifunctional protein.

              Sixty-six years have elapsed since the discovery of fetuin in 1944, but its importance in mammalian physiology has only recently been appreciated. Fetuin, first isolated from fetal bovine serum and now most commonly known as either fetuin-A, alpha-2-HS-glycoprotein (recommended name by UniprotKB and PIR), or α2-Heremans-Schmid glycoprotein, functions as an important component of diverse normal and pathological processes, including vascular calcification and bone metabolism regulation, insulin resistance, protease activity control, keratinocytes migration, and breast tumor cell proliferative signaling. Fetuin-A has also been identified as a biomarker for neurodegenerative disease. Here, we summarize recent publications focusing on the structural and functional properties of fetuin-A. The emerging importance of fetuin-A for both diagnosis and therapeutics has come to the attention of the pharmaceutical industry. Therefore, we will discuss the status of patents based on fetuin-A.
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                Author and article information

                Journal
                Diab Vasc Dis Res
                Diab Vasc Dis Res
                DVR
                spdvr
                Diabetes & Vascular Disease Research
                SAGE Publications (Sage UK: London, England )
                1479-1641
                1752-8984
                18 September 2019
                November 2019
                : 16
                : 6
                : 562-576
                Affiliations
                [1 ]Institute of Cellular Biology and Pathology ‘Nicolae Simionescu’, Bucharest, Romania
                [2 ]Internal Medicine Clinic, Emergency Clinical Hospital, Bucharest, Romania
                [3 ]Clinical Department of Internal Medicine, University of Medicine and Pharmacy of Targu Mures, Targu Mures, Romania
                [4 ]Clemson University, Clemson, SC, USA
                Author notes
                [*]Adriana Georgescu, Institute of Cellular Biology and Pathology ‘Nicolae Simionescu’, 8 B.P. Hasdeu Street, District 5, PO Box 35-14, 050568 Bucharest, Romania. Email: adriana.georgescu@ 123456icbp.ro
                [*]

                M.M.T. and A.F. contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-4945-1745
                Article
                10.1177_1479164119874469
                10.1177/1479164119874469
                6787765
                31530180
                f1915b95-9574-4f1d-8fb0-9cdfe2263157
                © The Author(s) 2019

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Funding
                Funded by: academia româna, FundRef https://doi.org/10.13039/501100006476;
                Funded by: programa operacional temático factores de competitividade, FundRef https://doi.org/10.13039/501100011929;
                Award ID: Financing Contract no.115/13.09.2016/ MySMIS:10436
                Categories
                Original Articles

                Endocrinology & Diabetes
                diabetes,cardiovascular aortic valve disease,aortic valve,inflammatory markers,extracellular matrix remodelling,osteogenic markers

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