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AGE-MD2 complexes in serum and cardiac tissues in diabetes. a Levels of AGE products in heart tissues of type 1 mouse model of diabetes. C57BL/6 wild-type and MD2KO mice were made diabetic by streptozotocin. Heart tissues were harvested at 16 weeks and levels of AGE products were determined by ELISA [experimental groups are as described in Fig. 2; means ± SEM; n = 6 per group]. b Representative blots showing coimmunoprecipitation of MD2-AGE complexes in heart tissues from type 1 mouse model of diabetes. Tissues from WT-Con and WT-STZ mice at 16 weeks after confirmation of diabetes were examined [n = 6; two samples per group shown]. c MD2-AGE complexes were measured in serum of WT-Con and WT-STZ mice at 16 weeks [means ± SEM; n = 4]. d Levels of AGE products in heart tissues of type 2 mouse model of diabetes. Heart tissues from db/m (controls) and db/db (diabetic) mice were harvested at 16 weeks. AGE products were determined by ELISA [means ± SEM; n = 5 per group]. e Representative blots showing co-immunoprecipitation of MD2-AGE complexes in heart tissues from type 2 mouse model of diabetes [experimental groups are as shown in panel D; n = 6; two samples per group shown]. f MD2-AGE complexes were measured in serum of db/m and db/db mice at 16 weeks [means ± SEM; n = 5]. g Serum levels of AGE products in healthy human subjects and diabetic subjects with cardiomyopathy [Co = healthy subjects (n = 8), DCM = diabetic subjects with cardiomyopathy (n = 9); means ± SEM]. h Representative blots showing AGE-MD2 complexes in human blood mononuclear cells isolated from healthy subjects (Con) and diabetic subjects (n = 6; two samples per group shown). i MD2-AGE complexes in serum samples from human subjects [means ± SEM; n = 3 per group]. Source data are provided as a Source Data file. P-values by one-way ANOVA in a followed by Tukey's post hoc test are indicated. P-values by unpaired t test are indicated in c, d, f, g and i.

AGE-MD2 complexes in serum and cardiac tissues in diabetes. a Levels of AGE products in heart tissues of type 1 mouse model of diabetes. C57BL/6 wild-type and MD2KO mice were made diabetic by streptozotocin. Heart tissues were harvested at 16 weeks and levels of AGE products were determined by ELISA [experimental groups are as described in Fig. 2; means ± SEM; n = 6 per group]. b Representative blots showing coimmunoprecipitation of MD2-AGE complexes in heart tissues from type 1 mouse model of diabetes. Tissues from WT-Con and WT-STZ mice at 16 weeks after confirmation of diabetes were examined [n = 6; two samples per group shown]. c MD2-AGE complexes were measured in serum of WT-Con and WT-STZ mice at 16 weeks [means ± SEM; n = 4]. d Levels of AGE products in heart tissues of type 2 mouse model of diabetes. Heart tissues from db/m (controls) and db/db (diabetic) mice were harvested at 16 weeks. AGE products were determined by ELISA [means ± SEM; n = 5 per group]. e Representative blots showing co-immunoprecipitation of MD2-AGE complexes in heart tissues from type 2 mouse model of diabetes [experimental groups are as shown in panel D; n = 6; two samples per group shown]. f MD2-AGE complexes were measured in serum of db/m and db/db mice at 16 weeks [means ± SEM; n = 5]. g Serum levels of AGE products in healthy human subjects and diabetic subjects with cardiomyopathy [Co = healthy subjects (n = 8), DCM = diabetic subjects with cardiomyopathy (n = 9); means ± SEM]. h Representative blots showing AGE-MD2 complexes in human blood mononuclear cells isolated from healthy subjects (Con) and diabetic subjects (n = 6; two samples per group shown). i MD2-AGE complexes in serum samples from human subjects [means ± SEM; n = 3 per group]. Source data are provided as a Source Data file. P-values by one-way ANOVA in a followed by Tukey's post hoc test are indicated. P-values by unpaired t test are indicated in c, d, f, g and i.

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Hyperglycemia activates toll-like receptor 4 (TLR4) to induce inflammation in diabetic cardiomyopathy (DCM). However, the mechanisms of TLR4 activation remain unclear. Here we examine the role of myeloid differentiation 2 (MD2), a co-receptor of TLR4, in high glucose (HG)- and diabetes-induced inflammatory cardiomyopathy. We show increased MD2 in h...

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... next assessed whether MD2 deficiency prevents infiltration of macrophages in the heart. We stained heart tissues for CD68 and show increased immunoreactivity in WT-STZ mice compared with WT-Con ( Supplementary Fig. 7a). CD68 immunoreactivity was reduced in heart tissues of MD2KO-STZ mice, suggesting decreased infiltration. ...
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... immunoreactivity was reduced in heart tissues of MD2KO-STZ mice, suggesting decreased infiltration. Immunoblotting also showed increased CD68 protein levels in heart lysates prepared from WT-STZ mice but not MD2KO-STZ mice ( Supplementary Fig. 7b). Furthermore, MD2KO-STZ mice showed no induction of inflammatory cell adhesion molecules ICAM1 and VCAM1 ( Supplementary Fig. 7b). ...
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... also showed increased CD68 protein levels in heart lysates prepared from WT-STZ mice but not MD2KO-STZ mice ( Supplementary Fig. 7b). Furthermore, MD2KO-STZ mice showed no induction of inflammatory cell adhesion molecules ICAM1 and VCAM1 ( Supplementary Fig. 7b). These findings suggest that MD2 deficiency reduces adhesion molecules involved in macrophage recruitment and prevents macrophage infiltration in diabetes. ...
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... AGE interaction with MD2 to activate MD2-TLR4 signaling complex. To explore this complex formation in animal models of diabetes and in human subjects, we first determined the levels of AGE products. Measurement of AGE content in myocardial tissues of STZ-induced type 1 diabetic mice showed a twofold increase over levels in non-diabetic controls (Fig. 7a). Serum levels of AGE products were also increased in WT-STZ mice (Supplementary Fig. 26a). No changes in AGE content was observed in MD2KO-STZ mice compared with WT-STZ mice. Consistent with our cell culture studies, no increases in MGO and CML levels were noted in control and diabetic mice (Supplementary Fig. 26b-c). MD2 antibody ...
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... Fig. 26a). No changes in AGE content was observed in MD2KO-STZ mice compared with WT-STZ mice. Consistent with our cell culture studies, no increases in MGO and CML levels were noted in control and diabetic mice (Supplementary Fig. 26b-c). MD2 antibody pulled down increased amounts of AGE and TLR4 in lysates prepared from WT-STZ mice (Fig. 7b), suggesting increased MD2-AGE and MD2-TLR4 complex formation. Since MD2 also exists in a soluble form (sMD2) and appears to be important for sensing endogenous ligands 31,32 , we speculated that circulating sMD2 and AGEs may form complexes in the context of diabetes. We detected serum sMD2-AGEs complexes using a sandwich ELISA and show ...
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... in a soluble form (sMD2) and appears to be important for sensing endogenous ligands 31,32 , we speculated that circulating sMD2 and AGEs may form complexes in the context of diabetes. We detected serum sMD2-AGEs complexes using a sandwich ELISA and show approximately twofold higher content of MD2-AGE complexes in WT-STZ mice compared with WT-Con (Fig. 7c). Parallel analyses were made in a type 2 diabetic mouse model (db/db). Analysis of cardiac tissues in db/db mice showed increased AGE levels (Fig. 7d), enhanced MD2-AGE and MD2-TLR4 complexes (Fig. 7e), and MD2-AGE complexes in serum (Fig. 7f), compared with non-diabetic db/m controls. Furthermore, as with the STZinduced model of type ...
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... in the context of diabetes. We detected serum sMD2-AGEs complexes using a sandwich ELISA and show approximately twofold higher content of MD2-AGE complexes in WT-STZ mice compared with WT-Con (Fig. 7c). Parallel analyses were made in a type 2 diabetic mouse model (db/db). Analysis of cardiac tissues in db/db mice showed increased AGE levels (Fig. 7d), enhanced MD2-AGE and MD2-TLR4 complexes (Fig. 7e), and MD2-AGE complexes in serum (Fig. 7f), compared with non-diabetic db/m controls. Furthermore, as with the STZinduced model of type 1 diabetes, myocardial tissue of db/db mice showed increased levels of TNF-α, IL-6, and MD2 levels compared with db/m controls ( Supplementary Fig. ...
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... sMD2-AGEs complexes using a sandwich ELISA and show approximately twofold higher content of MD2-AGE complexes in WT-STZ mice compared with WT-Con (Fig. 7c). Parallel analyses were made in a type 2 diabetic mouse model (db/db). Analysis of cardiac tissues in db/db mice showed increased AGE levels (Fig. 7d), enhanced MD2-AGE and MD2-TLR4 complexes (Fig. 7e), and MD2-AGE complexes in serum (Fig. 7f), compared with non-diabetic db/m controls. Furthermore, as with the STZinduced model of type 1 diabetes, myocardial tissue of db/db mice showed increased levels of TNF-α, IL-6, and MD2 levels compared with db/m controls ( Supplementary Fig. ...
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... and show approximately twofold higher content of MD2-AGE complexes in WT-STZ mice compared with WT-Con (Fig. 7c). Parallel analyses were made in a type 2 diabetic mouse model (db/db). Analysis of cardiac tissues in db/db mice showed increased AGE levels (Fig. 7d), enhanced MD2-AGE and MD2-TLR4 complexes (Fig. 7e), and MD2-AGE complexes in serum (Fig. 7f), compared with non-diabetic db/m controls. Furthermore, as with the STZinduced model of type 1 diabetes, myocardial tissue of db/db mice showed increased levels of TNF-α, IL-6, and MD2 levels compared with db/m controls ( Supplementary Fig. ...
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... interaction is evident in human subjects with diabetes. Blood was collected from healthy subjects, and diabetic subjects with or without evidence of DCM. We isolated peripheral blood mononuclear cells (PBMCs) and prepared serum. Analysis of serum content of AGE products showed 2-fold greater levels in DCM subjects compared with healthy subjects (Fig. 7g). Interestingly, we observed that HG addition to healthy human serum significantly induces AGE production within 5 min (Supplementary Fig. 28a), which is consistent with our finding that HG rapidly produces AGE in culture media containing serum ( Fig. 5a-d). In addition to increased serum AGE levels, PBMCs isolated from diabetic ...
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... Fig. 28a), which is consistent with our finding that HG rapidly produces AGE in culture media containing serum ( Fig. 5a-d). In addition to increased serum AGE levels, PBMCs isolated from diabetic subjects with DCM or without cardiomyopathy showed elevated levels of MD2 proteins ( Supplementary Fig. 28b), and increased AGE-MD2-TLR4 complexes (Fig. 7h). Analysis of serum samples further showed elevated soluble MD2 ( Supplementary Fig. 28c), inflammatory cytokines TNF-α and IL-6 ( Supplementary Fig. 28d-e), and MD2-AGE complexes (Fig. 7i) in diabetic subjects with DCM and without cardiomyopathy, compared with healthy samples. Our identification of increased MD2-AGE complexes in ...
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... diabetic subjects with DCM or without cardiomyopathy showed elevated levels of MD2 proteins ( Supplementary Fig. 28b), and increased AGE-MD2-TLR4 complexes (Fig. 7h). Analysis of serum samples further showed elevated soluble MD2 ( Supplementary Fig. 28c), inflammatory cytokines TNF-α and IL-6 ( Supplementary Fig. 28d-e), and MD2-AGE complexes (Fig. 7i) in diabetic subjects with DCM and without cardiomyopathy, compared with healthy samples. Our identification of increased MD2-AGE complexes in diabetic mice and human subjects extended the findings obtained from in vitro studies, and strengthen the idea that direct AGE-MD2 interactions are the initiating events driving the cardiac ...

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