Shun Xu

A TagSNP in SIRT1 Gene Confers Susceptibility to Myocardial Infarction in a Chinese Han Population

SIRT1 exerts protective effects against endothelial cells dysfunction, inflammation and atherosclerosis, indicating an important role on myocardial infarction (MI) pathogenesis. Nonetheless, the effects of SIRT1 variants on MI risk remain poorly understood. Here we aimed to investigate the influence of SIRT1 polymorphisms on individual susceptibility to MI. Genotyping of three tagSNPs (rs7069102, rs3818292 and rs4746720) in SIRT1 gene was performed in a Chinese Han population, consisting of 287 MI cases and 654 control subjects. In a logistic regression analysis, we found that G allele of rs7069102 had increased MI risk with odds ratio (OR) of 1.57 [95% confidence interval (CI) = 1.15–2.16, Bonferroni corrected P (Pc) = 0.015] after adjustment for conventional risk factors compared to C allele. Similarly, the combined CG/GG genotypes was associated with the increased MI risk (OR = 1.64, 95% CI = 1.14–2.35, Pc = 0.021) compared to the CC genotype. Further stratified analysis revealed a more significant association with MI risk among younger subjects (≤ 55 years old). Consistent with these results, the haplotype rs7069102G-rs3818292A-rs4746720T containing the rs7069102 G allele was also associated with the increased MI risk (OR = 1.41, 95% CI = 1.09–1.84, Pc = 0.040). However, we did not detect any association of rs3818292 and rs4746720 with MI risk. Our study provides the first evidence that the tagSNP rs7069102 and haplotype rs7069102G-rs3818292A-rs4746720T in SIRT1 gene confer susceptibility to MI in the Chinese Han population.

The LRP6 rs2302685 polymorphism is associated with increased risk of myocardial infarction

BackgroundAbnormal lipids is one of the critical risk factors for myocardial infarction (MI), however the role of genetic variants in lipid metabolism-related genes on MI pathogenesis still requires further investigation. We herein genotyped three SNPs (LRP6 rs2302685, LDLRAP1 rs6687605, SOAT1 rs13306731) in lipid metabolism-related genes, aimed to shed light on the influence of these SNPs on individual susceptibility to MI.MethodsGenotyping of the three SNPs (rs2302685, rs6687605 and rs13306731) was performed in 285 MI cases and 650 control subjects using polymerase chain reaction–ligation detection reaction (PCR–LDR) method. The association of these SNPs with MI and lipid profiles was performed with SPSS software.ResultsMultivariate logistic regression analysis showed that C allele (OR = 1.62, P = 0.039) and the combined CT/CC genotype (OR = 1.67, P = 0.035) of LRP6 rs2302685 were associated with increased MI risk, while the other two SNPs had no significant effect. Further stratified analysis uncovered a more evident association with MI risk among younger subjects (≤60 years old). Fascinatingly, CT/CC genotype of rs2302685 conferred increased LDL-C levels compared to TT genotype (3.0 mmol/L vs 2.72 mmol/L) in younger subjects.ConclusionsOur data provides the first evidence that LRP6 rs2302685 polymorphism is associated with an increased risk of MI in Chinese subjects, and the association is more evident among younger individuals, which probably due to the elevated LDL-C levels.

Identification of the lncRNA, AK156230, as a novel regulator of cellular senescence in mouse embryonic fibroblasts

Long noncoding RNAs (lncRNAs) have gained extensive attentions in recent years because of their potential importance in a variety of biological and pathological processes. In this study, we sought to explore the role of lncRNAs in cellular senescence. Here, we report that the lncRNA AK156230 was downregulated during replicative senescence in mouse embryonic fibroblasts (MEFs), and knockdown of AK156230 promotes a robust senescence phenotype, including increase in the numbers of the senescence-associated β-galactosidase-positive cells, decrease of cell proliferation, accumulation of cells in the G2/M phase and reduction of autophagic activity. The cells with knockdown AK156230 expression also exhibited increased levels of p21, p53 and phosphorylated p53, and a decreased activity of CDK1. Moreover, rapamycin-induced autophagy offered cytoprotective effect and rescued cellular senescence in AK156230 knockdown cells. Gene expression profile showed that the dysregulation of autophagy and cell cycle genes contributed to the induction of cellular senescence after AK1561230 silencing. Taken together, these results suggest that downregulation of AK156230 is involved in the induction of cellular senescence through its roles in autophagy and cell cycle progression. Our study identifies AK156230 as a critical lncRNA that has a role in regulating cellular senescence in MEFs.

MicroRNA-33 promotes the replicative senescence of mouse embryonic fibroblasts by suppressing CDK6

MicroRNAs are a large class of tiny noncoding RNAs, which have emerged as critical regulators of gene expression, and thus are involved in multiple cellular processes, including cellular senescence. MicroRNA-33 has previously been established to exert crucial effect on cell proliferation, lipid metabolism and cholesterol metabolism. Nonetheless, the association between microRNA-33 and cellular senescence and its underlying molecular mechanism are far to be elucidated. The present study has attempted to probe into the effect of microRNA-33 on MEFs senescence. Our data unveiled that microRNA-33 was dramatically down-regulated in senescent MEFs compared to the young MEFs, and ectopic expression of microRNA-33 promoted MEFs senescence, while knock-down of microRNA-33 exhibited a protective effect against senescence phenotype. Moreover, we verified CDK6 as a direct target of microRNA-33 in mouse. Silencing of CDK6 induced the premature senescence phenotype of MEFs similarly as microRNA-33, while enforced expression of CDK6 significantly reverse the senescence-induction effect of microRNA-33. Taken together, our results suggested that microRNA-33 enhanced the replicative senescence of MEFs potentially by suppressing CDK6 expression.

miR‑342‑5p promotes Zmpste24‑deficient mouse embryonic fibroblasts proliferation by suppressing GAS2

Cellular senescence is an irreversible growth arrest of cells that maintain their metabolic activities. Premature senescence can be induced by different stress factors and occurs in mouse embryonic fibroblasts (MEFs) derived from Zmpste24 metalloproteinase-deficient mice, a progeria mouse model of Hutchinson-Gilford Progeria Syndrome. Previous studies have shown that miR-342-5p, an intronic microRNA (miRNA/miR) reportedly involved in ageing associated diseases, is downregulated in Zmpste24−/− MEFs. However, whether miR-342-5p is associated with the premature senescence phenotype of Zmpste24−/− MEFs remains unclear. Thus, the present study investigated the effects of miR-342-5p on cellular senescence and cell proliferation in Zmpste24−/− MEFs. The results showed that miR-342-5p overexpression ameliorated the cellular senescence phenotype to a certain extent, promoted cell proliferation and increased the G2+M cell cycle phase in Zmpste24−/− MEFs. Nonetheless, it was difficult to observe the opposite cell phenotypes in wild-type (WT) MEFs transfected with the miR-342-5p inhibitor. Growth-arrest-specific 2 (GAS2) was identified as a target gene of miR-342-5p in Zmpste24−/− MEFs. In addition, miR-342-5p was identified to be downregulated in WT MEFs during replicative senescence, while Gas2 was upregulated. Taken together, these findings suggest that downregulated miR-342-5p is involved in regulating cell proliferation and cell cycles in Zmpste24−/− MEFs by suppressing GAS2 in vitro.

Two tagSNPs rs352493 and rs3760908 within SIRT6 Gene Are Associated with the Severity of Coronary Artery Disease in a Chinese Han Population

SIRT6 has been demonstrated to exert protective effects on endothelial cells and is closely associated with lipid metabolism, glucose metabolism, and obesity, indicating an important role in the pathogenesis and progression of coronary artery disease (CAD). Nonetheless, the biological significance of SIRT6 variants on CAD is far to be elucidated. Here we aimed to investigate the influence of SIRT6 polymorphisms on individual susceptibility and severity of CAD. Multivariate logistic regression analysis exhibited no significant association between these five polymorphisms and CAD risk in the genotype and allele frequencies. However, we found that the rs352493 polymorphism in SIRT6 exhibited a significant effect on the severity of CAD; C allele (χ 2 = 7.793, adjusted P = 0.013) and the combined CC/CT genotypes (χ 2 = 5.609, adjusted P = 0.031) presented the greater CAD severity. In addition, A allele (χ 2 = 5.208, adjusted P = 0.046) and AA (χ 2 = 4.842, adjusted P = 0.054) of rs3760908 were also associated with greater CAD severity in Chinese subjects. Our data provided the first evidence that SIRT6 tagSNPs rs352493 and rs3760908 play significant roles in the severity of CAD in Chinese Han subjects, which might be useful predictors of the severity of CAD.

The Impact of tagSNPs in CXCL16 Gene on the Risk of Myocardial Infarction in a Chinese Han Population

CXCL16 has been demonstrated to be involved in the development of atherosclerosis and myocardial infarction (MI). Nonetheless, the role of the CXCL16 polymorphisms on MI pathogenesis is far to be elucidated. We herein genotyped four tagSNPs in CXCL16 gene (rs2304973, rs1050998, rs3744700, and rs8123) in 275 MI patients and 670 control subjects, aimed at probing into the impact of CXCL16 polymorphisms on individual susceptibility to MI. Multivariate logistic regression analysis showed that C allele (OR = 1.31, 95% CI = 1.03–1.66, and P = 0.029) and CC genotype (OR = 1.84, 95% CI = 1.11–3.06, and P = 0.018) of rs1050998 were associated with increased MI risk; and C allele (OR = 0.77, 95% CI = 0.60–0.98, and P = 0.036) of rs8123 exhibited decreased MI risk, while the other two tagSNPs had no significant effect. Consistently, the haplotype rs2304973T-rs1050998C-rs3744700G-rs8123A containing the C allele of rs1050998 and A allele of rs8123 exhibited elevated MI risk (OR = 1.41, 95% CI = 1.02–1.96, and P = 0.037). Further stratified analysis unveiled a more apparent association with MI risk among younger subjects (≤60 years old). Taken together, our results provided the first evidence that CXCL16 polymorphisms significantly impacted MI risk in Chinese subjects.

miR‐194 functions as a novel modulator of cellular senescence in mouse embryonic fibroblasts

MicroRNA‐194 (miR‐194), a typical p53 responsive miRNA, serves as a tumor suppressor similar as p53, and has been demonstrated to play an anti‐proliferation role in various human cancers. In spite of the pivotal role of p53 during aging process, the knowledge of miR‐194s contribution to cellular senescence is limited. We herein sought to explore the role of miR‐194 in the replicative senescence and stress‐induced senescence of mouse embryonic fibroblasts. Our results unraveled that, compared to young cells, miR‐194 is highly expressed in senescent cells, and extra expression of miR‐194 significantly triggers the replicative senescence of MEFs and H2O2‐induced senescence of NIH/3T3 cells, while inhibition of miR‐194 exhibited the opposite effect. We further unveiled that DNMT3A was a direct and authentic target of miR‐194, which has been reported to be closely associated with cellular senescence. Taken together, our data suggest that miR‐194 may significantly promote the development of cellular senescence in mouse embryonic fibroblasts, which potentially occurs through inhibiting the DNMT3A expression.