Sex-dependent association of phosphodiesterase 4D gene polymorphisms with ischemic stroke in Henan Han population

Background Recent evidence has implicated the gene for phosphodiesterase 4D （PDE4D） as susceptibility gene for ischemic stroke （IS） in Icelandic population. However, there are few reports on the associations between PDE4D gene polymorphisms and IS in Chinese individuals. The present study aimed to investigate the possible association of genetic polymorphisms in PDE4D gene with IS in Henan Han population. Methods A total of 400 patients with IS and 400 matched controls were examined using a case-control design. Two single nucleotide polymorphism （SNPs） （rs918592 and rs2910829） in PDE4D gene were genotyped by polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） method. Odds ratios （OR） and 95% confidence intervals （95% CI） were calculated to test the association between the genetic factors and IS. Genetic parameter and association studies were carried out with SPSS 16.0. Results Among the two SNPs tested, the rs918592 was significantly associated with IS （OR： 1.351, 95% CI： 1.110-1.645）, especially in male patients （OR： 1.427, 95% CI： 1.105-1.844）. Haplotype analysis showed that A-T was associated with an increased risk of the IS （OR： 2.114, 95% CI： 2.005-2.230） while G-T was associated with decreased risk of IS （OR： 0.419, 95% CI： 0.302--0.583）. Protecting effect of haplotype G-T was also significant in males （OR： 0.264, 95% Cl： 0.162-0.431）. Conclusions The present study demonstrated a strong association of rs918592 with IS. Haplotype A-T increased the risk of IS while haplotype G-T had a protective effect in Henan Han population. The association was sex-dependent with male patients showing stronger effect.

Association of ALOX5AP and PDE4D with the risk of lacunar infarct in people from Jiangsu Province,China

The genes for 5-1ipoxygenase activating protein （ALOX5AP） and phosphodiesterase 4D （PDE4D） have been demonstrated as susceptibility genes for lacunar in the Icelandic and Pakistani populations, but little is known about the role of these genes in Chinese populations. The present study utilized polymerase chain reaction and ligase detection reaction to detect single nucleotide polymorphisms （SNPs） in 280 consecutive stroke patients and 258 unrelated population-based controls from Nanjing, Jiangsu Province, China. The allele frequency, genotypes, and haplotypes of the two SNPs （rs456009 and rs966221） in PDE4D were similar between the two groups. However, A allele frequency of rs4073259 （A/G） and rs4769055 （A/C） in the ALOX5AP gene exhibited differences in two groups, and especially the haplotype of the SNP was significantly different between the two groups. Results suggested that the ALOX5AP gene might be involved in lacunar infarct, while PDE4D gene was not a risk factor for lacunar infarct in individuals from Jiangsu Province, China.

Role of PDE4D splice variants in the mediation of antidepressant and cognition-enhancing actions and its mechanisms

OBJECTIVE Phosphodiesterase 4(PDE4),specific for cyclicAMP(cAMP)-hydrolyzing,has four isoforms(PDE4A-D) with at least 25 splice variants. PDE4 inhibitors produce definite antidepressant-like and cognitive-enhancing effects. However,none of PDE4 inhibitors has yet been approved for clinical utility so far due to the concomitant side effects. The present research is to explore the splice variants of PDE4 D responsible for antidepressant-like and cognitive-enhancing effects of PDE4 inhibitors but not side effects. METHODS Long-form PDE4 Ds were silenced by the bilateral microinfusion of lentiviral vector containing mi RNAs(4Dmi R) into the prefrontal cortex(PFC),PDE4D4 or D5 was overexpressed by the bilateral microinfusion of lentiviral vector containing full c DNA into hippocampus. Antidepressant-like behaviors were measured by tail-suspension test(TST),forced swimming test(FST)and chronic unpredictable stress model. Cognitive behaviors were measured by the novel object recognition test(NOR) and Morris water maze test(MWM) in both normal mice and the mice with chronic unpredictable stress-induced memory deficits. The emetic potential was evaluated by the assessment of the anaesthetic reversal effect,a surrogate of the emesis test in non-vomiting species. The expressions of PDE4 isoforms/splice variants and cAMP level were examined by Western-blot and ELISA analysis. The dendritic complexity and spine density were assessed by Golgi staining. RESULTS(1)High and specific expression of EGFP(green,indicator of 4Dmi R expression) in PFC was observed under fluorescence microscopy.(2) 4Dmi R significantly down-regulated PDE4D4/5 splice variants,but not PDE4 A,PDE4 B or PDE4D1/2/3.(3) 4Dmi R treatments significantly increased cAMP signaling and dendritic complexity in PFC.(4) Rolipram and/or 4Dmi R treatments significantly decreased immobility in TST and FST.(5) Rolipram and/or 4Dmi R treatments reversed the depressive-like behaviors in chronically stressed mice,including the reduced sucrose preference,prolonged latency to novelty-suppressed feeding and increased immobility in FST.(6) Rolipram and/or 4Dmi R treatments significantly increased the recognition index in NOR task and both the entries and durations in MWM task.(7) Rolipram and/or 4Dmi R treatments reversed the memory deficits in chronically stressed mice,including the reduced the recognition index in NOR task and the decreased durations in MWM task.(8) Rolipram and/or 4DmiR treatments reversed the decreased cA MP signaling,dendritic complexity and spine density.(9) Rolipram or plus 4Dmi R treatment significantly decreased the duration of anaesthesia in the alpha2 adrenergic receptor-mediated anesthesia,but not 4Dmi R treatment alone.(10)Hippocampal overexpression of PDE4D5,but not PDE4D4,produced depressive-like and cognitive defect behaviors,which were reversed by rolipram.The measurements including cAMP signaling,dendritic complexity and in vivo hippocampal LTP,showed the same changes. CONCLUSION Long-form PDE4 Ds,especially the PDE4D5,are the major isoforms responsible for antidepressant-like and cognitive-enhancing effects with little side effects. The critical roles of long-form PDE4 Ds are mediated by their regulation of cAMP signaling pathway and neuroplasticity.