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Arterial media calcification is associated with diabetes mellitus. Previous studies have shown that advanced glycation end products (AGEs) are responsible for vascular smooth muscle cell (VSMC) calcification, but the underlying mechanisms remain unclear. Hypoxia-inducible factor-1α (HIF-1α), one of the major factors during hypoxia, and pyruvate dehydrogenase kinase 4 (PDK4), an important mitochondrial matrix enzyme in cellular metabolism shift, have been reported in VSMC calcification. The potential link among HIF-1α, PDK4, and AGEs-induced vascular calcification was investigated in this study. We observed that AGEs elevated HIF-1α and PDK4 expression levels in a dose-dependent manner and that maximal stimulation was attained at 24 h. Two important HIF-1α-regulated genes, vascular endothelial growth factor A (VEGFA) and glucose transporter 1 (GLUT-1), were significantly increased after AGEs exposure. Stabilization or nuclear translocation of HIF-1α increased PDK4 expression. PDK4 inhibition attenuated AGEs-induced VSMC calcification, which was evaluated by measuring the calcium content, alkaline phosphatase (ALP) activity and runt-related transcription factor 2 (RUNX2) expression levels and by Alizarin red S staining. In addition, the glucose consumption, lactate production, key enzymes of glucose metabolism and oxygen consumption rate (OCR) were decreased during AGEs-induced VSMC calcification. In conclusion, this study suggests that AGEs accelerate vascular calcification partly through the HIF-1α/PDK4 pathway and suppress glucose metabolism.

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BackgroundBrain-derived neurotrophic factor (BDNF) is a neurotrophin involved in angiogenesis and maintenance of endothelial integrity. Whether circulating BDNF levels are associated with von Willebrand factor (vWF) levels, which are indicators of endothelial dysfunction is not known. This study investigated the association between plasma BNDF and vWF levels and whether these biomarkers could predict cardiovascular events at a 12-month follow-up in patients with stable coronary artery disease (CAD).MethodsWe recruited 234 patients with suspected angina pectoris. Subjects were divided into CAD (n = 143) and control (n = 91) groups based on coronary angiography. Plasma BDNF and vWF levels were measured using ELISA. Patients were followed-up for one year, and information on adverse cardiac events was collected.ResultsCAD patients exhibited significantly lower plasma BDNF and higher vWF levels than those of control patients. High vWF levels were associated with low BDNF levels even after adjustment for age, gender, low-density lipoprotein (LDL) levels, and the presence of diabetes mellitus. A receiver operating characteristic curve was used to determine whether low BDNF and high vWF levels could predict adverse cardiovascular events. The area under the curve for vWF and the inverse of BDNF were 0.774 and 0.804, respectively.ConclusionsThese findings suggest that endothelial dysfunction is an important determinant of the impaired circulating BDNF levels, and they further reflected cardiovascular prognosis in stable CAD patients.

The 'obesity paradox' does exist in patients after coronary revascularization, especially for patients with post-percutaneous coronary intervention. All-cause mortality in patients with high BMI is significantly lower compared with patients with normal weight. Furthermore, patients with underweight experience higher rates of cardiovascular outcomes compared with patients with normal weight.

Background: The osteogenic differentiation of vascular smooth muscle cell (VSMCs) is important for the development of vascular calcification (VC), particularly in diabetes. Exosomes derived from Mesenchymal Stromal Cells (MSCs) are effective against cardiovascular diseases, yet their role in VC remains unclear. Advanced glycation end products (AGEs) inhibit bone marrow stromal cell osteogenesis by targeting osteogenesis-associated genes. Thus, we investigated the role of exosomes derived from MSCs pretreated with AGEs-BSA in VC and its potential mechanisms.Methods: Primary VSMCs and MSCs were isolated from the aorta and bone marrow of Sprague-Dawley rats, respectively. VSMCs were cultured with AGEs-BSA to induce osteogenic differentiation. Exosomes were harvested from MSCs by ultracentrifugation. MSCs and VSMCs were cocultured in Transwells, and exosomes were added to VSMC culture medium to assess their effects on osteogenic differentiation. Double luciferase reporter assay was applied to confirm that miR-146a directly targets the 3' UTR of the thioredoxin-interacting protein (TXNIP) gene.Results: Pretreatment of VSMCs with AGEs-BSA increased the expression of thioredoxin-interacting protein (TXNIP) by inhibiting that of miR-146a, resulting in enhanced ROS production and VSMC calcification. By contrast, the expression of miR-146a in MSCs was increased by AGEs-BSA treatment. Thus, miR-146a was transferred from AGEs-BSA-pretreated or miR-146a-transfected MSCs to VSMCs via exosomes. After coculture with miR-146a-containing exosomes, the AGEs-BSA-mediated increase in VSMC calcification was diminished, accompanied by decreased TXNIP expression and ROS production. Furthermore, TXNIP overexpression counteracted the anti-calcification effects of MSC-derived miR-146a-containing exosomes. In addition, TXNIP was identified as a target gene of miR-146a, and the results of double luciferase reporter assay confirmed that TXNIP was the direct target gene of miR-146a.Conclusions: Exosomes secreted by MSCs pretreated with AGEs-BSA contained a high level of miR-146a, which was transferred to VSMCs and inhibited AGEs-BSA-induced calcification in a TXNIP-dependent manner. Thus, miR-146a-containing exosomes may be a potential therapeutic target for VC.