Gender differences in the association of syndecan-4 with myocardial infarction: The population-based Tromsø Study

Solbu, Marit Dahl; Kolset, Svein Olav; Jenssen, Trond; Wilsgaard, Tom; Løchen, Maja‐Lisa; Mathiesen, Ellisiv B.; Melsom, Toralf; Eriksen, Bjørn Odvar; Reine, Trine M.

doi:10.1016/j.atherosclerosis.2018.08.005

Cited by 26 publications

(27 citation statements)

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“…Considering that the relationship between body fat mass and various cardiometabolic risk factors also vary by sex in humans [60], our results may have a high relevance to human health. This is further supported by observations from a recent study, showing that serum levels of SDC4 were significantly associated with myocardial infarction in women [61]. In addition, high levels of SDC4 gene expression are significantly associated with estrogen receptor-positive breast carcinomas [62], corroborating the notion of a relationship between SDC4 and estrogen/estrogen receptor signaling.…”

Section: Discussionsupporting

confidence: 80%

Genetic Deletion of Syndecan-4 Alters Body Composition, Metabolic Phenotypes, and the Function of Metabolic Tissues in Female Mice Fed A High-Fat Diet

et al. 2019

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Syndecans are transmembrane proteoglycans that, like integrins, bind to components of the extracellular matrix. Previously, we showed significant associations of genetic variants in the Syndecan-4 (SDC4) gene with intra-abdominal fat, fasting plasma glucose levels, and insulin sensitivity index in children, and with fasting serum triglyceride levels in healthy elderly subjects. An independent study also reported a correlation between SDC4 and the risk of coronary artery disease in middle-aged patients. Here, we investigated whether deletion of Sdc4 promotes metabolic derangements associated with diet-induced obesity by feeding homozygous male and female Sdc4-deficient (Sdc4-/-) mice and their age-matched wild-type (WT) mice a high-fat diet (HFD). We found that WT and Sdc4-/- mice gained similar weight. However, while no differences were observed in males, HFD-fed female Sdc4-/- mice exhibited a higher percentage of body fat mass than controls and displayed increased levels of plasma total cholesterol, triglyceride, and glucose, as well as reduced whole-body insulin sensitivity. Additionally, they had an increased adipocyte size and macrophage infiltration in the visceral adipose tissue, and higher triglyceride and fatty acid synthase levels in the liver. Together with our previous human genetic findings, these results provide evidence of an evolutionarily conserved role of SDC4 in adiposity and its complications.

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Section: Discussionsupporting

confidence: 80%

Genetic Deletion of Syndecan-4 Alters Body Composition, Metabolic Phenotypes, and the Function of Metabolic Tissues in Female Mice Fed A High-Fat Diet

et al. 2019

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“…MV were recovered in medium from untreated cells, most likely indicating spontaneous release of MV during cellular homeostatic processes and is consistent with detection of the presence of low number of endothelium-derived MV in the circulation of healthy humans [27]. Except for PECAM-1, under control condition, there were greater numbers of MV in conditioned media derived from female than from male cells, perhaps reflecting differences in glycocalyx structure or cellular metabolism [39, 40].…”

Section: Discussionsupporting

confidence: 73%

Sex differences in the expression of cell adhesion molecules on microvesicles derived from cultured human brain microvascular endothelial cells treated with inflammatory and thrombotic stimuli

2019

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Background There are sex differences in risk for stroke and small vessel ischemic disease in the brain. Microvesicles (MV) derived from activated cells vary by cell of origin and the stimulus initiating their release. MV released from cells activated by inflammatory and thrombotic factors have the potential to disrupt endothelial cells of the brain microvasculature. Therefore, experiments were designed to identify sex differences in the phenotype of MV released from cultured human brain microvascular endothelial cells (HBMEC) in response to inflammatory and thrombotic stimuli. Methods Cultured HBMEC derived from 20- to 30-year-old male and female donors were treated for 20 h with medium supplemented with tumor necrosis factor alpha (TNFα; 20 ng/ml), thrombin (THR; 2 U/ml), or vehicle (i.e., control). MV were isolated from the conditioned media by high-speed centrifugation and quantified by digital flow cytometry by labeling with fluorophore-conjugated primary antibodies against PECAM-1, integrin αvβ3, ICAM-1, E-selectin, or MCAM. In addition, temporal uptake of labeled MV into control HBMEC was examined by confocal microscopy. Results Under control conditions, male HBMEC released fewer MV expressing each antigen, except for PECAM-1, than female cells ( P < 0.05). Neither TNFα nor THR reduced cell viability. However, TNFα induced apoptosis in female and male cells, whereas THR increased apoptosis marginally only in male cells. TNFα increased expression of all antigens tested on MV in male cells, but only increased expression of integrin αvβ3, ICAM-1, and E-selectin on MV from female cells. THR increased expression of PECAM-1, ICAM-1, and MCAM-1 on MV from male but not female cells. MV were internalized and localized to lysosomes within 90 min after their application to HBMEC. Conclusions There are sex differences in expression of cell adhesion molecules on MV released from HBMEC under control conditions and upon activation by TNFα or THR. MV taken up by unstimulated HBMEC may impact the integrity of the brain microvasculature and account, in part, for sex differences in vascular pathologies in the brain.

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“…We have also shown that increased serum concentrations of syndecan-1 are related to early diabetic nephropathy [18], and we observed a trend for increased syndecan-1 serum concentrations in hyperglycemic individuals compared to normoglycemic kidney transplanted patients together with increased levels of the syndecan sheddase matrix metalloproteinase MMP-9 [19]. Furthermore, we have demonstrated high expression of syndecan-4 in endothelial cells [20], and in a case-cohort study including 1500 participants from the Tromsø study, we observed that serum syndecan-4 was an independent predictor of myocardial infarction [21]. Although syndecan-shedding is reported to be increased in chronic hyperglycemia, shedding of syndecans in prediabetes has not been studied to a great extent.…”

Section: Introductionmentioning

confidence: 62%

Acute exercise increases syndecan-1 and -4 serum concentrations

et al. 2019

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Gender differences in the association of syndecan-4 with myocardial infarction: The population-based Tromsø Study

Cited by 26 publications

References 46 publications

Genetic Deletion of Syndecan-4 Alters Body Composition, Metabolic Phenotypes, and the Function of Metabolic Tissues in Female Mice Fed A High-Fat Diet

Genetic Deletion of Syndecan-4 Alters Body Composition, Metabolic Phenotypes, and the Function of Metabolic Tissues in Female Mice Fed A High-Fat Diet

Sex differences in the expression of cell adhesion molecules on microvesicles derived from cultured human brain microvascular endothelial cells treated with inflammatory and thrombotic stimuli

Acute exercise increases syndecan-1 and -4 serum concentrations

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