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We investigated whether type 2 diabetes concomitant to aortic stenosis (AS) enhances valvular inflammation and coagulation activation via upregulated expression of NF-\u03baB, with subsequent increased expression of bone morphogenetic protein 2 (BMP-2).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this case\u2013control study, 50 individuals with severe isolated AS and concomitant type 2 diabetes were compared with a control group of 100 individuals without diabetes. The median (IQR) duration of diabetes since diagnosis was 11 (7\u201318) years, and 36 (72%) individuals had HbA\n                      <jats:sub>1c<\/jats:sub>\n                      \u226548 mmol\/mol (\u22656.5%). Stenotic aortic valves obtained during valve replacement surgery served for in loco NF-\u03baB, BMP-2, prothrombin (FII) and active factor X (FXa) immunostaining. In vitro cultures of valve interstitial cells (VICs), isolated from obtained valves were used for mechanistic experiments and PCR investigations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Diabetic compared with non-diabetic individuals displayed enhanced valvular expression of NF-\u03baB, BMP-2, FII and FXa (all\n                      <jats:italic>p<\/jats:italic>\n                      \u2009\u2264\u20090.001). Moreover, the expression of NF-\u03baB and BMP-2 positively correlated with amounts of valvular FII and FXa. Only in diabetic participants, valvular NF-\u03baB expression was strongly associated with serum levels of HbA\n                      <jats:sub>1c<\/jats:sub>\n                      , and moderately with fructosamine. Of importance, in diabetic participants, valvular expression of NF-\u03baB correlated with aortic valve area (AVA) and maximal transvalvular pressure gradient. In vitro experiments conducted using VIC cultures revealed that glucose (11\u00a0mmol\/l) upregulated expression of both NF-\u03baB and BMP-2 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). In VIC cultures treated with glucose in combination with reactive oxygen species (ROS) inhibitor (\n                      <jats:italic>N<\/jats:italic>\n                      -acetyl-\n                      <jats:sc>l<\/jats:sc>\n                      -cysteine), the expression of NF-\u03baB and BMP-2 was significantly suppressed. A comparable effect was observed for VICs cultured with glucose in combination with NF-\u03baB inhibitor (BAY 11\u20137082), suggesting that high doses of glucose activate oxidative stress leading to proinflammatory actions in VICs. Analysis of mRNA expression in VICs confirmed these findings; glucose caused a 6.9-fold increase in expression of\n                      <jats:italic>RELA<\/jats:italic>\n                      (NF-\u03baB p65 subunit), with the ROS and NF-\u03baB inhibitor reducing the raised expression of\n                      <jats:italic>RELA<\/jats:italic>\n                      by 1.8- and 3.2-fold, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>\n                      Type 2 diabetes enhances in loco inflammation and coagulation activation within stenotic valve leaflets. Increased valvular expression of NF-\u03baB in diabetic individuals is associated not only with serum HbA\n                      <jats:sub>1c<\/jats:sub>\n                      and fructosamine levels but also with AVA and transvalvular gradient, indicating that strict long-term glycaemic control is needed in AS patients with concomitant type 2 diabetes. This study suggests that maintaining these variables within the normal range may slow the rate of AS progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-021-05545-w","type":"journal-article","created":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T15:02:21Z","timestamp":1631026941000},"page":"2562-2574","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Diabetes concomitant to aortic stenosis is associated with increased expression of NF-\u03baB and more pronounced valve calcification"],"prefix":"10.1007","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4026-8971","authenticated-orcid":false,"given":"Magdalena","family":"Kopytek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4077-1232","authenticated-orcid":false,"given":"Piotr","family":"Mazur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1762-308X","authenticated-orcid":false,"given":"Micha\u0142","family":"Z\u0105bczyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3716-1724","authenticated-orcid":false,"given":"Anetta","family":"Undas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3176-8007","authenticated-orcid":false,"given":"Joanna","family":"Natorska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,7]]},"reference":[{"issue":"5","key":"5545_CR1","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1016\/0735-1097(93)90249-Z","volume":"21","author":"M Lindroos","year":"1993","unstructured":"Lindroos M, Kupari M, Heikkil\u00e4 J, Tilvis R (1993) Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. 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