MicroRNA-17-5p Promotes Vascular Calcification by Targeting ANKH.

BACKGROUND: MicroRNAs (miRNAs) may participate in the process of vascular calcification. However, the role of microRNA-17-5p in vascular calcification has not been clarified. In this study, we showed the effects of microRNA-17-5p on vascular calcification. MATERIALS AND METHODS: Vascular smooth muscle cells (VSMCs) were transfected with miR-17-5p mimics, a miR-17-5p inhibitor or negative control (NC) using Lipofectamine 2000. Then the cells were induced by an osteogenic medium. Alkaline phosphatase (ALP) activity and mineralization were determined. Osteocalcin (OC), bone morphogenetic protein 2(BMP-2), Collagen Ia (Colla), Runx2, and ankylosis protein homolog (ANKH) gene expressions were determined by reverse transcription-polymerase chain reaction. Vascular calcification was developed using a renal failure model. RESULTS: The ALP activity was increased when miR-17-5p mimics were transfected, whereas the miR-17-5p inhibitor reduced ALP activity (p < 0.05). The number and average area of mineral nodes in the miR-17-5p mimic group was larger than those in the corresponding control and NC groups (p < 0.05). The number and average area of the mineral nodes in the miR-17-5p inhibitor group were smaller than those in the corresponding control and NC groups (p < 0.05). Bmp2, OC, Col1a and Runx2 were higher in the miR-17-5p mimics group compared to those in the control and NC groups. ANKH expression was decreased in VSMCs with the miR-17-5p mimics and increased in VSMCs with miR-17-5p inhibitor. ANKH siRNA intervention also promoted mineralization. The miR-17-5p expression was upregulated and ANKH was down-regulated in the aortic arteries with calcification. CONCLUSION: Our data showed that miR-17-5p may promote vascular calcification by inhibiting ANKH expression.

HNF1α Controls Liver Lipid Metabolism and Insulin Resistance via Negatively Regulating the SOCS-3-STAT3 Signaling Pathway.

This study is aimed at evaluating the effects, functions, and mechanism of HNF1α on hepatic glycolipid metabolism. In this study, free fatty acid- (FFA-) induced steatosis of hepatocyte liver cell LO2 was used as an in vitro model. The methods of Oil Red O staining, RT-qPCR, western blot, and immunofluorescence staining were used to detect LO2-regulated HNF1α expression and its effects on FFA-induced LO2 cell steatosis, the insulin signaling and SOCS-3-STAT3 signaling pathways, the expression of lipid metabolism-related regulators, and phosphorylation. With increased FFA induction time, the expression of HNF1α in the LO2 fatty degeneration hepatic cells gradually decreased. Downregulation of HNF1α expression aggravated FFA-induced steatosis of LO2 hepatocytes. HNF1α promotes activation of the insulin pathway and oxidative breakdown of fat and inhibits lipid anabolism. Inhibitors of STAT3 can reverse the regulation of decreased HNF1α expression on the insulin signaling pathway and fat metabolism. We also confirmed this pathway using HNF1α-/- mice combining treatment with STAT3 inhibitor NSC 74859 in vivo. HNF1α regulates hepatic lipid metabolism by promoting the expression of SOCS-3 and negatively regulating the STAT3 signaling pathway.

Prehypertension is associated with atherosclerosis in Type 2 diabetes.

BACKGROUND: Prehypertension is a risk factor for hypertension, diabetes, and cardiovascular diseases. However, the association between prehypertension and atherosclerosis in Type 2 diabetes mellitus (T2DM) has not been evaluated. In the present study, we investigated the impact of prehypertension on atherosclerosis in T2DM. METHODS: Patients (n=930) with T2DM were recruited for the present study from the outpatient clinic of Shanghai Ruijin Hospital. The intima-media thickness (IMT) of the common carotid artery (CCA) was determined using ultrasound and brachial-ankle pulse wave velocity (baPWV) was determined by volume plethysmography to assess atherosclerosis. RESULTS: Of the 930 patients with T2DM (mean age of 59 years), 167 were categorized as normotensive, 213 were prehypertensive, and 550 were hypertensive. Diabetic subjects with prehypertension had significantly higher CCA-IMT and baPWV than those with normal blood pressure after adjustment for age and gender. Multiple logistic regression analysis revealed that, compared with normotension, prehypertension was a significant independent determinant of atherosclerosis (for maximum IMT ≥1.1 mm, odds ratio (OR) 2.10 and 95% confidence interval (CI) 1.28-3.44; for baPWV ≥1400 cm/s, OR 3.09 and 95% CI 1.78-5.36). CONCLUSION: Prehypertension is associated with atherosclerosis independent of conventional cardiovascular risk factors in T2DM patients. We speculate that maintenance of systolic blood pressure <120 mmHg and diastolic blood pressure <80 mmHg may reduce the risk of atherosclerosis in T2DM.

Serum C-reactive protein (CRP) and microalbuminuria in relation to fasting and 2-h postload plasma glucose in a Chinese population.

OBJECTIVE: Serum C-reactive protein (CRP) and microalbuminuria are predictors of cardiovascular disease. The association of these factors of cardiovascular risk with fasting and 2-h postload plasma glucose in a group of Chinese subjects was investigated. DESIGN: This was a cross-sectional cohort study. SUBJECTS AND METHODS: In 1776 subjects randomly selected from the permanent residents of a community in the city of Shanghai, China, a simplified 75-g oral glucose tolerance test (fasting and 2-h postload blood sampling only) was performed, and serum CRP concentrations and urinary albumin : creatinine ratio were measured. RESULTS: Serum CRP concentration significantly increased from 1.62 mg/l in normoglycaemic subjects to 2.63 mg/l in subjects with impaired glucose regulation, and to 3.09 mg/l in newly diagnosed diabetic patients (P < 0.0001). The corresponding prevalence of microalbuminuria also increased from 4.3% to 6.6% and to 11.4% (P < 0.0001). Both before and after adjustment for confounders, fasting and 2-h postload plasma glucose levels were significantly associated with serum CRP concentration and the risk of microalbuminuria (P < 0.003). However, the association for CRP tended to be more prominent with 2-h postload plasma glucose than with fasting plasma glucose. Indeed, with adjustments applied, for 1 SD change in fasting and 2-h postload plasma glucose concentration, serum CRP concentration increased by 14% and 18% (between the two regression coefficients, P = 0.01), respectively. With similar adjustments, for 1 SD change in fasting and 2-h postload plasma glucose concentration, the odds of microalbuminuria increased by 28% and 32% (P = 0.28 for the difference between 28% and 32%), respectively. CONCLUSIONS: Our finding suggests that in Chinese plasma glucose, especially 2-h postload, is associated with biological markers of cardiovascular disease, such as serum CRP concentration and microalbuminuria.

Zinc transporter-8 gene (SLC30A8) is associated with type 2 diabetes in Chinese.

CONTEXT: Several genome-wide association studies identified a strong association of SLC30A8 with type 2 diabetes in individuals of European ancestry. The effect of the association of rs13266634 with type 2 diabetes or related glycemic traits has not been fully extended to non-European populations, and a comprehensive examination of common variants in the gene has not yet been carried out in Han Chinese. OBJECTIVE: The objective of the study was to investigate the association of SLC30A8 with type 2 diabetes in Chinese. DESIGN: A comprehensive gene-based association study was performed using 14 tagging single-nucleotide polymorphism (SNPs) of SLC30A8 in Han Chinese subjects with normal glucose tolerance (NGT; n = 721), impaired glucose regulation (IGR; n = 375), and type 2 diabetes (n = 521). RESULTS: A significant association for SNP rs13266634 was observed between patients with type 2 diabetes and NGT controls (P = 0.016). The association was also observed between combined type 2 diabetes/IGR and NGT subjects (P = 0.002). The adjusted odds ratios for homozygote CC vs. TT at this locus were 1.71 for type 2 diabetes (95% confidence interval 1.19-2.45, P = 0.002) and 1.77 for type 2 diabetes and IGR (95% confidence interval 1.29-2.42, P = 0.0001). We further studied the genotype-phenotype correlation in 70 Han Chinese using iv glucose tolerance test and found an association between SNP rs13266634 and acute insulin response to glucose and disposition index (adjusted P = 0.012 and 0.004, respectively). CONCLUSIONS: Our results provide evidence that SLC30A8 is a susceptible locus for type 2 diabetes in Chinese population, and its variant can influence insulin secretion.