Identification and Regulation of Human PDE5A Gene Promoter

Lin, Chen; Chow, Samson A.; Lau, Andy T. Y.; Tu, Richard; Lue, Tom F.

doi:10.1006/bbrc.2000.4220

Cited by 67 publications

(60 citation statements)

References 25 publications

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“…8 Analysis of gene fragments preceding each of these three exons identified two promoters: one preceding and overlapping with the A1-specific exon (the PDE5A promoter) and another preceding the A2-specific exon (the PDE5A2 promoter). 8,9 The PDE5A promoter consists of a 139-bp core with full basal activity, a 308-bp upstream enhancer, and a 156-bp downstream enhancer. The enhancers confer additive cyclic nucleotide-inducible activities to the basal promoter.…”

Section: Introductionmentioning

confidence: 99%

Tissue expression, distribution, and regulation of PDE5

Lin

2004

Int J Impot Res

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Phosphodiesterase 5 (PDE5) has been identified in many species. The three isoforms, PDE5A1, PDE5A2, and PDE5A3, differ only in their N-terminal sequence. PDE5A1 and PDE5A2 are ubiquitous, but PDE5A3 is specific to smooth muscle. The initial three exons (A1-A3-A2) of PDE5A, located on chromosome 4q26, are alternative first exons encoding the isoform-specific sequences. The PDE5A promoter overlaps with the A1-specific exon, while the PDE5A2 promoter is located between the A3-and A2-specific exons. Both respond to cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate (cAMP) stimulation. The PDE5A2 promoter contains an Sp1-binding sequence critical for basal and cGMP/cAMP-inducible promoter activities. PDE5A is induced by adjacent sequences (enhancers) containing Sp1-binding sites. The potential role of PDE5A promoters in the tachyphylaxis effect of PDE5 inhibitors is currently being investigated. Preliminary data suggest that hypoxia might down-regulate PDE5A promoters, implying an involvement of PDE5 in stuttering priapism.

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Section: Introductionmentioning

confidence: 99%

Tissue expression, distribution, and regulation of PDE5

Lin

2004

Int J Impot Res

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“…It is a key physiologic regulator of cGMP and pharmacologic target of vasodilatory drugs (such as sildenafil citrate) used commonly to treat PH and erectile dysfunction 8. The coding sequence, functional regions, and transcript variants of PDE5A are well described in human beings 9, 10. Additionally, the genetic sequence of phosphodiesterase genes has been demonstrated to be responsible for the selective action of some phosphodiesterase inhibiting agents.…”

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confidence: 99%

Identification of PDE5A:E90K: A Polymorphism in the Canine Phosphodiesterase 5A Gene Affecting Basal cGMP Concentrations of Healthy Dogs

Stern

Reina-Doreste

Chdid

et al. 2013

Veterinary Internal Medicne

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BackgroundCyclic guanosine monophosphate (cGMP)‐specific phosphodiesterase (PDE5A) is the target of phosphodiesterase inhibitors such as sildenafil. Polymorphisms in the PDE5A gene that may predict response to therapy with sildenafil and nitric oxide, be linked to disease progression, and aid in risk assessment have been identified in human beings. Identification of polymorphisms in PDE5A could affect the physiologic actions of PDE5A and the effects of phosphodiestrase type 5 inhibitor drugs.Hypothesis/ObjectiveFunctional polymorphisms exist in the canine PDE5A gene. Specific objectives were to identify PDE5A polymorphisms and evaluate their functional relevance.AnimalsSeventy healthy dogs.MethodsThe exonic, splice‐site, 3′ and 5′ untranslated regions of the canine PDE5A gene were sequenced in 15 dogs and aligned with the canine reference sequence. Identified polymorphisms were evaluated in 55 additional, healthy, unrelated dogs of 20 breeds. Plasma was collected from 51 of these dogs and cGMP was measured. An unpaired t‐test and one‐way ANOVA with Dunnett's test of multiple comparisons were used to evaluate the effect of genotype on cGMP.ResultsA common exonic polymorphism was identified that changed glutamic acid to lysine and resulted in significantly lower cGMP concentrations in the group with polymorphism versus the wild type group (P = .014). Additionally, 6 linked single nucleotide polymorphisms in the 3′ untranslated region were identified that did not alter cGMP concentrations.Conclusions and Clinical ImportanceA polymorphism exists in the canine PDE5A gene that is associated with variable circulating cGMP concentrations in healthy dogs and warrants investigation in diseases such as pulmonary hypertension.

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“…AF319172), from 86 bp upstream the initial ATG codon to more than 500 bp downstream the G(À1142)T polymorphism we identified. 27 Thus, it is possible that our polymorphism is not functional. This first approach to this relevant intermediate phenotype failed to find an association between PDE5 alleles and EH/ED.…”

Section: Discussionmentioning

confidence: 98%

“…23 The G allele we found is less frequent than the T allele, already described in literature, but all were similarly present both in hypertensive patients with ED and hypertensives without ED, without any difference in allele frequency between groups. While this work was in progress, several studies were published about organization and function of the PDE5A gene promoter: [26][27][28][29] the three isoforms of PDE5 (PDE5A1, 2 and 3), which differ only in the 5 0 ends of their mRNAs, are codified by three alternative first exons (arranged in the order A1-A3-A2). Transcription of these exons is regulated by two promoters: an intronic promoter for the PDE5A2 isoform and a more classical promoter in the 5 0 -flanking region for the other two isoforms.…”

Section: Discussionmentioning

confidence: 99%

“…Transcription of these exons is regulated by two promoters: an intronic promoter for the PDE5A2 isoform and a more classical promoter in the 5 0 -flanking region for the other two isoforms. 26,27 Analysis of this classic promoter shows that it is composed of a core promoter of 139 bp, an upstream regulatory region of 308 bp (containing AP2 and Sp1 elements) and a downstream regulatory region of 156 bp (containing several Sp1 elements). The entire promoter region ranges from 3115 to 3717 nucleotides (GenBank accession no.…”

Section: Discussionmentioning

confidence: 99%

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Cardiovascular effects of sildenafil in hypertensive men with erectile dysfunction and different alleles of the type 5 cGMP-specific phosphodiesterase (PDE5)

et al. 2004

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Erectile dysfunction (ED) is frequent in patients with essential hypertension (EH); a likely common pathogenetic pathway could be a reduced ability of arteriolar vascular smooth muscle (VSM) to relax. Increasing intracellular levels of cGMP reduce the contractile status of VSM; on the contrary, type 5 cGMP-specific phosphodiesterase (PDE5, codified by PDE5A gene) regulates cGMP levels through its clearance. The PDE5A gene represents a good candidate for the intermediate phenotype EH/ED: genetic variants of the PDE5A may predispose to EH and ED and could affect the local and systemic response to sildenafil administration. Thus, a functionally relevant portion of PDE5 5 0 -flanking promoter region was analyzed by PCR and direct sequencing in patients with EH and idiopathic ED. The sequences obtained showed a T/G polymorphism at position -1142, near an AP1 regulatory element, that was not apparently associated with the intermediate phenotype. We also studied the relationship between this polymorphism and the effects of oral sildenafil on blood pressure (BP) and heart rate (HR) in men with ED. Sildenafil caused a significant decrease of BP, but had no effects on HR; statistical analysis showed no differences in BP and HR variations among PDE5A genotypes. In conclusion, our data showed no correlations of a novel polymorphism of the PDE5A promoter gene with the intermediate phenotype EH/ED and the BP and HR response to sildenafil administration. Further studies are necessary to define the role of this polymorphism and to study the genetic predisposition for EH with ED.

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Identification and Regulation of Human PDE5A Gene Promoter

Cited by 67 publications

References 25 publications

Tissue expression, distribution, and regulation of PDE5

Tissue expression, distribution, and regulation of PDE5

Identification of PDE5A:E90K: A Polymorphism in the Canine Phosphodiesterase 5A Gene Affecting Basal cGMP Concentrations of Healthy Dogs

Cardiovascular effects of sildenafil in hypertensive men with erectile dysfunction and different alleles of the type 5 cGMP-specific phosphodiesterase (PDE5)

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