ABSTRACT
ABSTRACT Objective: Globally developing metabolic syndrome (MetS) prevalence as a major health problem can be related to multiple factors of genetic and environmental. Dimethylaminohydrolase 2 (DDAH2) is the main enzyme implicated in the cardiovascular system, which regulates the nitric oxide pathway. This study investigated the association of DDAH2 polymorphism −499C/G (rs805305) with the risk of MetS among the Azar-Cohort population. Subjects and methods: The occurrence of SNP rs805305 in the DDAH2 gene was tested using the PCR-RFLP method in 332 MetS cases and 294 healthy controls. Afterward, the association of the allele and genotypes with the risk of MetS and its components were examined. Results: The G allele and GC genotype were significantly associated with a reduced risk of MetS (P ≤ 0.001). Also, the dominant genetic model (GG+GC) significantly decreased the risk of MetS (P = 0.001), however, in sex subtypes MetS risk was significantly reduced in males before and in females after adjustment for age (P ≤ 0.02). Conclusion: The −499C/G polymorphism of DDAH2 may play a protective role and reduce MetS risk among the Azar-Cohort population.
Subject(s)
Humans , Male , Female , Metabolic Syndrome/genetics , Amidohydrolases/genetics , Polymorphism, Genetic , Case-Control Studies , Promoter Regions, Genetic , Genetic Predisposition to Disease/genetics , Polymorphism, Single Nucleotide/genetics , Protective Factors , GenotypeABSTRACT
Methylation modification is an important cellular mechanism of gene expression regulation. Dimethylarginine dimethylaminohydrolase-2 (DDAH-2) protein is a pivotal molecular for endothelium function. To explore the effects of 5-aza-deoxycytidine (5-aza), a demethylation agent, in hyperhomocysteinemia (hhcy)-related erectile dysfunction (ED) rats, 5-aza (1 mg kg-1 ) was administrated to Sprague-Dawley hhcy-rats induced by supplemented methionine chow diet. Erectile function, nitric oxide-cyclic guanosine monophosphate (NO-cGMP) levels, expression of DDAH-2 protein and promoter methylation status of DDAH-2 were studied in the corpora cavernosa. We found that supplemented methionine diet induced a high homocysteine level after 6 weeks of treatment. DDAH-2 protein was down-regulated in the corpora cavernosa while the administration of 5-aza up-regulated DDAH-2 expression and restored erectile function. The methionine-fed rats showed high methylation levels of DDAH-2 promoter region while the group treated with 5-aza demonstrated lower-methylation levels when compared to the methionine-fed group. Besides, the administration of 5-aza improved NO and cGMP levels in methionine-fed rats. Therefore, the methylation mechanism involves in ED pathogenesis, and demethylation offers a potential new strategy for ED treatment.
ABSTRACT
Objective To investigate the pulmonary microvascular responsiveness of diabetic animals to sepsis and the potential mechanism of NO system.Methods Sixty-four Wistar rats of clean grade were randomly (random number) divided into 4 groups,namely normal control group (group A,n =16),diabetes group (group B,n =16),sepsis group (group C,n =16),diabetes and sepsis group (group D,n =16).Diabetic mellitus model was made in rats with injection of streptozotocin,STZ (65 mg/kg).Successful model was defined as the blood glucose value≥ 16.67 mmol/L 48 hours after injection of STZ.All animals were fed 4 weeks before initiation of next experiment.The sepsis model was established by intravenous injection of LPS (10 mg/kg) in rats.RT-PCR was used to determine the mRNA expression of Tie-2 in rats'blood.The ratio of dry/wet of lung tissue and the extravasation of Evans blue dye into the lung were detected.Quantitation of NO in lung tissue and serum was measured by using Griess method.RT-PCR was also used for determination of iNOS,eNOS,DDAH2 mRNA expressions in lung tissue.Data were analyzed with ANONA and LSD method for comparison between groups,and P ＜ 0.05 was considered statistically significant.Results Compared with septic group.,the diabetic rats with sepsis group demonstrated higher expression of Tie-2 mRNA in blood (19.72 ± 0.70) vs.(3.99 ± 0.92),P =0.00,lower ratio of dry/wet in lung tissue (0.19 ±0.01) vs.(0.22 ±0.01),P =0.000,higher permeability of Evans blue dye into lung tissue (3.76 ± 0.77) vs.(1.74 ± 0.24),P =0.000.Serum NO level was lower in group D than that in group C (123.13 ±4.24) vs.(188.30 ±5.18),P =0.000,however,NO levels in lung tissue of both group D and group C were higher than that in control group (53.62 ± 6.70),(23.63± 3.92) vs.(10.37 ± 1.29),P =0.00,and NO level in group D was higher in 2 times than that in group C (P =0.00).However,there were no differences in eNOS expression among groups A,B and C,but the difference in eNOS expression was present between group D with lower expression and group A,that lower in group D (0.07 ±0.02) vs.(0.38 ±0.05),P=0.017.Compared with group C,the expression of iNOS was higher in group D (80.23 ±2.49),(32.48±5.37) vs.(1.74±0.23),P=0.00),and the expression of DDAH2 was lower in group D (0.49 ±0.13),(7.26 ±0.50) vs.(11.96 ±0.55).Conclusions Diabetic rats with sepsis enhanced endothelial cell damages.Diabetes deteriorates the regulatory activity of NO system,suggesting the potential mechanism of the worsened damages of EC in diabetic sepsis host.