Reduced folic acid levels, alcohol consumption, and the MTHFR 677T and 1298C alleles may have contributed to NSCLP development in this sample population from Rio Grande do Norte.
These results suggest that polymorphisms at LEP, LEPR, and MC4R may be useful biomarkers of obesity-related cardiometabolic alterations in our population.
BackgroundNitric oxide (NO) has been largely associated with cardiovascular protection
through improvement of endothelial function. Recently, new evidence about
modulation of NO release by microRNAs (miRs) has been reported, which could be
involved with statin-dependent pleiotropic effects, including anti-inflammatory
properties related to vascular endothelium function.ObjectiveTo evaluate the effects of cholesterol-lowering drugs including the inhibitors of
cholesterol synthesis, atorvastatin and simvastatin, and the inhibitor of
cholesterol absorption ezetimibe on NO release, NOS3 mRNA expression and miRs
potentially involved in NO bioavailability.MethodsHuman umbilical vein endothelial cells (HUVEC) were exposed to atorvastatin,
simvastatin or ezetimibe (0 to 5.0 μM). Cells were submitted to
total RNA extraction and relative quantification of NOS3 mRNA and
miRs -221, -222 and -1303 by qPCR. NO release was measured in supernatants by
ozone-chemiluminescence.ResultsBoth statins increased NO levels and NOS3 mRNA expression but no
influence was observed for ezetimibe treatment. Atorvastatin, simvastatin and
ezetimibe down-regulated the expression of miR-221, whereas miR-222 was reduced
only after the atorvastatin treatment. The magnitude of the reduction of miR-221
and miR-222 after treatment with statins correlated with the increment in
NOS3 mRNA levels. No influence was observed on the miR-1303
expression after treatments.ConclusionNO release in endothelial cells is increased by statins but not by the inhibitor
of cholesterol absorption, ezetimibe. Our results provide new evidence about the
participation of regulatory miRs 221/222 on NO release induction mediated by
statins. Although ezetimibe did not modulate NO levels, the down-regulation of
miR-221 could involve potential effects on endothelial function.
This study explored circulating miRNAs and target genes associated with metabolic syndrome (MetS) and cardiometabolic risk in obese patients. Small-RNA sequencing was used to assess the peripheral blood miRNome of 12 obese subjects (6 MetS and 6 non-MetS). Differentially expressed miRNAs and target genes were further analyzed by qPCR in a larger sample of obese patients (48 MetS and 32 non-MetS). miRNA:mRNA interactions were studied using in silico tools. miRNome analysis identified 10 downregulated miRNAs in MetS compared to non-Met patients (p < 0.05). In silico studies revealed three miRNAs (miR-155, miR-181a, and let-7a) and their predictive targets (CCAAT/enhancer-binding protein beta—CEBPB, KRAS proto-oncogene, GTPase—KRAS and suppressor of cytokine signaling 1—SOCS1) with a potential role in the insulin receptor signaling pathway. miR-155 expression was reduced and CEBPB mRNA levels were increased in MetS patients (p < 0.05), and these effects were correlated with the number of MetS diagnostic criteria (p < 0.05). Increased HOMA-IR (>7.6) was associated with low miR-155 levels, high CEBPB expression, and serum hsCRP (p < 0.05). miR-155 was negatively correlated with CEBPB, HOMA-IR, and plasma fibrinogen, and positively correlated with serum adiponectin (p < 0.05). Downregulation of circulating miR-155 is associated with insulin resistance, poor glycemic control, and increased MetS-related cardiometabolic risk, and these effects are potentially mediated by interaction with CEBPB.
BackgroundPolymorphisms in genes encoding adiponectin (ADIPOQ) and interleukin-6 (IL6) have been associated with adiposity and obese-related phenotypes. This study investigated the relationship of ADIPOQ and IL6 gene polymorphisms with pro-inflammatory and cardiometabolic markers in obese patients.MethodsAnthropometric and body composition parameters were measured in 249 Brazilian subjects (30 to 68 yr). Metabolic and inflammatory markers and adipokines were analyzed in blood samples. ADIPOQ rs2241766 (45 T > G) and IL6 rs1800795 (−174G > C) polymorphisms were analyzed by real-time PCR and PCR-RFLP, respectively.ResultsType 2 diabetes, hypertension, dyslipidemia and increased values of waist circumference, body fat, leptin, fibrinogen, IL-1β, hsCRP and TNFα were related to obesity (p < 0.05). Multiple linear regression analysis showed a positive correlation between BMI and waist circumference, body fat, leptin, fibrinogen, PAI-1, IL-1β, hsCRP and TNFα values (p < 0.001) but not with adiponectin. Obese group had altered metabolic status, resistance to leptin and insulin, and atherogenic and pro-inflammatory profiles. ADIPOQ and IL6 variants were not directely related to obesity, leptin resistance or alterations in cardiometabolic markers. Individuals carrying ADIPOQ 45G allele (TG + GG genotype) had higher IL-6, IL-1β and TNFα levels than TT genotype carriers (p < 0.05). IL6 -174GG genotype was associated with increased IL-1β levels (p = 0.033).ConclusionObesity is associated with leptin resistance, cardiometabolic alterations and a pro-inflammatory status. Our results are suggestive that ADIPOQ and IL6 polymorphisms contribute to cardiometabolic risk in obese individuals.
SUMMARYIntroduction: Cholesterol-lowering therapy has been related with several pleiotropic effects including anti-inflammatory action in vascular endothelium; however, their influence on monocyte adhesion molecules is poorly described. Aims: To investigate the effect of inhibitors of synthesis (statins) and absorption (ezetimibe) of cholesterol on expression of adhesion molecules L-selectin, PSGL-1, VLA-4, LFA-1, and Mac-1 in mononuclear cells in vivo and in vitro using THP-1 cells. Methods: The influence of simvastatin (10 mg/day), ezetimibe (10 mg/day), and their combination (10 mg each/day) on mRNA expression of adhesion molecules was analyzed in peripheral blood mononuclear cells (PBMC) from hypercholesterolemics. The effects of atorvastatin, simvastatin, and ezetimibe on mRNA and protein expression of adhesion molecules were also evaluated in THP-1 cells. Results: Simvastatin/ezetimibe combination, but not the monotherapies, reduced the mRNA expression of the PSGL-1, LFA-1, and Mac-1 genes in PBMC from hypercholesterolemics. Total and LDL cholesterol in serum correlated with PSGL-1 mRNA expression, whereas HDL cholesterol negatively correlated with mRNA levels of L-selectin and VLA-4 genes (P < 0.05). Plasma hsCRP was also correlated with mRNA levels of VLA-4, LFA-1, and Mac-1 (P < 0.05). Atorvastatin and simvastatin at 10 lM reduced mRNA and protein expression of L-selectin, PSGL-1, and VLA-4 in THP-1 cells (P < 0.05). Conclusion: Cholesterol-lowering therapy modulates gene expression of adhesion molecules in PBMC from hypercholesterolemics and THP-1 cells. Simvastatin/ezetimibe combination gives more benefits by reducing to a larger extent the expression of adhesion molecules in mononuclear cells.
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