Background/Aims: Matrix metalloproteinase 9 (MMP9), a potent endopeptidase degrading extracellular matrix, plays a pivotal role in the pathogenesis of ischaemic stroke (IS). The present study was undertaken to determine the association of MMP9 gene polymorphisms and the risk of IS in a southern Chinese population. Methods: A cohort of 1274 patients and 1258 age-matched healthy controls were genotyped to detect the four MMP9 polymorphisms (rs17156, rs3787268, rs3918241 and rs3918242) using SNaPshot. Results: Our study demonstrated a significant difference in the genotype and allele frequencies of the MMP9 rs3918242 polymorphism between the IS patients and the controls (P = 0.012 for the genotype and P = 0.0092 for the allele). Stratification by smoking status showed statistically significant differences in the frequency and allele of the rs3918242 polymorphism between IS patients and the controls (P = 0.0052 for the genotype and P = 0.0019 for the allele). Further stratification by IS subtypes revealed that the presence of the T allele of the MMP9 rs3918242 polymorphism confers a higher risk of the large artery atherosclerosis subtype of IS (P = 0.017). Moreover, IS patients with the rs3918242 T allele of MMP9 presented with increased serum MMP9 production, and this increase was more significant in smokers with IS (P = 0.022). Patients carrying the variant T allele of the MMP9 rs3918242 polymorphism exhibited significantly higher infarct volumes than those with the major CC genotype (P = 0.036). Conclusion: Our study provides preliminary evidence that the MMP9 rs3918242 polymorphism is linked to a higher risk of IS, confirming the role of MMP9 in the pathophysiology of IS, with potentially important therapeutic implications.
Previous studies have suggested that microRNA-186 (miR-186) can be induced under hypoxic conditions, and is associated with apoptosis. This study was undertaken to explore the exact role of this microRNA (miRNA) in the apoptotic death of neurons during cerebral ischemic/reperfusion (I/R) injury. To model cerebral ischemia/reperfusion (I/R) injuries, we utilized a transient middle cerebral artery occlusion approach in rats, as well as a model of oxygen-glucose deprivation/reoxygenation (OGD/R) in Neuro2a cells. We found that in both in vitro and in vivo models of cerebral I/R injuries, levels of miR-186 were markedly decreased. When we overexpressed miR-186, this was associated with a reduction in the apoptotic death of neuroblastoma cells in the OGD/R model system, whereas the opposite was true when this miRNA was instead inhibited. We further found miR-186 to directly target hypoxia-inducible factor 1α (HIF-1α) by interacting with the 3′-untranslated region of this mRNA. When we knocked down HIF-1α, this partially overcame the apoptotic death of cells in response to OGD/R injury and associated miR-186 downregulation.Our findings indicate that miR-186 is able to reduce ischemic injury to neurons at least in part through downregulating HIF-1α, suggesting that the miR-186/HIF-1α axis is a potential therapeutic target for the treatment of ischemic stroke.
Emerging evidence suggests that the multiligand receptor for advanced glycation end products (RAGE) and its ligand high mobility group box 1 protein (HMGB1) contribute to the pathophysiology of ischaemic stroke (IS). The present study aimed to investigate the association of RAGE and HMGB1 variants with the risk of IS. A total of 1,034 patients and 1,015 age- and sex-matched healthy controls were genotyped to detect five genetic variants of the RAGE gene and four genetic variants of the HMGB1 gene using the Multiplex SNaPshot assay. We found that the rs2070600 variant of RAGE was associated with an increased risk of IS (OR = 1.19, 95% CI: 1.02-1.38, P = 0.043), whereas the rs2249825 variant of HMGB1 was associated with a decreased risk of IS (OR = 0.83, 95% CI: 0.71-0.98, P = 0.041). Further stratification by IS subtypes revealed that the presence of the TT genotype of the RAGE rs2070600 variant confers a higher risk of the large artery atherosclerosis subtype of IS (P = 0.036). Moreover, patients with the variant T allele of the RAGE rs2070600 variant presented with reduced serum soluble RAGE production. Patients carrying the variant G allele of the HMGB1 rs2249825 variant exhibited significantly lower infarct volumes than those with the major CC genotype. These clues may help in the development of optimal personalized therapeutic approaches for IS patients.
Large-scale genome-wide association analyses show an association between ADAMTS7 variations and coronary risk. However, the link between ADAMTS7 variability and ischaemic stroke (IS) has yet to be determined. This study evaluated ADAMTS7 variants with respect to the risk of IS. Genetic association analyses were performed in two independent case-control cohorts with 1279 patients with IS and 1268 age-matched healthy controls. Four variant genotypes of the ADAMTS7 gene were identified using the Multiplex SNaPshot assay. The rs3825807, rs11634042, and rs7173743 variants of ADAMTS7 were related to lower IS risk in both initial and replication cohort. The G-T-T-C and G-T-C-C haplotypes are significantly less prevalent in the IS group than in the control group. Further stratification according to IS subtypes indicated that carriers with the variant alleles of the rs3825807, rs11634042 and rs7173743 variants of ADAMTS7conferred a lower risk of developing large-artery atherosclerosis stroke subtype. Also, the mutated rs3825807 G allele, as well as the mutated rs11634042 T allele of ADAMTS7, are linked to a significant reduction of ADAMTS7 in patients with IS. Our findings confirm the role of ADAMTS7 in the pathophysiology of IS, with potentially significant implications for the prevention, treatment, and development of novel therapies for IS.
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