Gestational diabetes induces alterations of sirtuins in fetal endothelial cells

Abstract

Background: Gestational diabetes (GDM) has long-term consequences for the offspring. Sirtuins (SIRTs) are associated with vascular and metabolic functions. We studied the impact of GDM on SIRT activity and expression in fetal endothelial colony-forming cells (ECFCs) and human umbilical vein endothelial cells (HUVECs) from pregnancies complicated by GDM. Methods: ECFCs and HUVECs were isolated from cord and cord blood of 10 uncomplicated pregnancies (NPs) and 10 GDM pregnancies. Nicotinamidadenindinukleotid (NAD + ) concentration, SIRT1 and SIRT3 activity, transcription levels of SIRT1, SIRT3, and SIRT4, and protein levels of SIRT1, SIRT3, and SIRT4 were determined in vitro with or without SIRT activators resveratrol (RSV) and paeonol. results: Fetal ECFCs from GDM pregnancies showed a decreased NAD + concentration, reduced SIRT1 and SIRT3 activity, and lower transcription levels of SIRT1, SIRT3, and SIRT4. HUVECs from GDM pregnancies had decreased NAD + concentrations and transcription levels of SIRT1 and SIRT4. RSV markedly enhanced the expression and activity of SIRTs in ECFCs and HUVECs, while paeonol was active only in ECFCs. conclusion: A reduction of SIRT activity and expression in fetal endothelial cells provides potential mechanistic insights into the pathophysiology of long-term cardiovascular complications observed in the offspring of GDM pregnancies. SIRT activators can increase SIRT activity in ECFCs, which opens perspectives for new therapeutic targets. a dverse events during fetal life have been implicated to induce fetal programming, which can result in chronic diseases (1). Especially gestational diabetes (GDM) of the mother has been associated with cardiovascular disease, metabolic syndrome, and obesity during later life in the offspring (2,3). The pathophysiological processes responsible for these late complications are largely unknown.Sirtuins (SIRTs) are important regulators of aging and metabolic diseases (4,5). Mammalian SIRTs belong to the histone deacetylase class III family comprising seven members (SIRT1-7), which require Nicotinamidadenindinukleotid (NAD + ) for their enzymatic activity (6). SIRT1 downregulation has been observed in peripheral blood mononuclear cells of individuals with impaired glucose tolerance (7,8). SIRT1 is known to regulate vascular endothelial cell functions (9). Furthermore, in vitro and in vivo studies demonstrated that a reduction in the number of endothelial progenitor cells (EPCs) under hyperglycemia is associated with reduced SIRT1 levels and activity (8,10). Endothelial cells regulate vascular tone and are the first fetal cells exposed to maternal hyperglycemia.In recent years, it has become evident that SIRT1 is a key player of EPC dysfunction in insulin resistance and metabolic syndrome (7,10,11). Overexpression of endothelium-specific SIRT1 protects against endothelial dysfunction induced by a high-fat diet and hyperglycemia (12,13). Recently, resveratrol (RSV) and paeonol (2′-Hydroxy-4′-methoxyacetophenone) have been shown to activate SIRTs and thus c...

BCL2 and miR-181a transcriptional alterations in umbilical-cord blood cells can be putative biomarkers for obesity

“…It was demonstrated that SIRT1 overexpression can improve glucose metabolism and insulin signaling [60]. On the other hand, oxidative stress and hyperglycemia can decrease SIRT1 protein and gene expression in diabetic patients [12,61]. Nevertheless, our data showed no alteration in SIRT1 expression in placental or umbilical-cord blood cells.…”

“…SIRT1 is an important determinant of human longevity and a positive regulator of telomere length through modulation of telomerase activity and homologous recombination repair [11]. Decreased expression was detected in fetal endothelial colony-forming cells from pregnancies complicated by GDM, and provided potential mechanistic insights into the pathophysiology of long-term cardiovascular complications observed in the offspring of GDM pregnancies [12]. Indeed, some studies have associated (sub)telomere maintenance and also mitochondrial biogenesis with SIRT1 and TP53 [13][14][15][16].…”

Impact of Short-Term Hypoxia on Sirtuins as Regulatory Elements in HUVECs

“…For SIRT1, modulation of expression was described via carboxyl terminus binding protein (CtBP) [52]. Furthermore, SIRT1 gene expression was regulated in hypoxia in a HIF-dependent manner [76]. The CREB (cAMP-responsive element protein-binding) protein was able to regulate SIRT1 expression in response to the NAD/NADH-levels [77].…”

The Functionality of Endothelial-Colony-Forming Cells from Patients with Diabetes Mellitus

“…These studies were carried out to provide some insight into the dysfunction associated with ECFCs exposed to a diabetic environment. The research on UC-ECFCs from G-DM pregnancies has shown that the diabetic intrauterine environment also reduces the number of UC-ECFC colonies and their functionality in the form of reduced tubulogenic capacity, reduced proliferation, reduced migration and that G-DM UC-ECFCs have reduced sirtuin1 and sirtuin3, which are involved with regulating cell metabolism and aging, compared to UC-ECFCs from healthy pregnancies [33,34]. Dincer [35] demonstrated that G-DM UC-ECFCs were less tolerant to hypoxic environments, resulting in increased senescence and decreased tubulogenesis in hypoxic conditions compared to ECFCs from healthy controls.…”