Редактирование: PDE1C (раздел)

==Publications==

{{medline-entry
|title=Phosphodiesterase 1 regulation is a key mechanism in vascular aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26464516
|abstract=Reduced nitric oxide (NO)/cGMP signalling is observed in age-related vascular disease. We hypothesize that this disturbed signalling involves effects of genomic instability, a primary causal factor in aging, on vascular smooth muscle cells (VSMCs) and that the underlying mechanism plays a role in human age-related vascular disease. To test our hypothesis, we combined experiments in mice with genomic instability resulting from the defective nucleotide excision repair gene [[ERCC1]] (Ercc1(d/-) mice), human VSMC cultures and population genome-wide association studies (GWAS). Aortic rings of Ercc1(d/-) mice showed 43% reduced responses to the soluble guanylate cyclase (sGC) stimulator sodium nitroprusside (SNP). Inhibition of phosphodiesterase (PDE) 1 and 5 normalized SNP-relaxing effects in Ercc1(d/-) to wild-type (WT) levels. [[PDE1C]] levels were increased in lung and aorta. cGMP hydrolysis by PDE in lungs was higher in Ercc1(d/-) mice. No differences in activity or levels of cGMP-dependent protein kinase 1 or sGC were observed in Ercc1(d/-) mice compared with WT. Senescent human VSMC showed elevated [[PDE1A]] and [[PDE1C]] and PDE5 mRNA levels (11.6-, 9- and 2.3-fold respectively), which associated with markers of cellular senescence. Conversely, PDE1 inhibition lowered expression of these markers. Human genetic studies revealed significant associations of [[PDE1A]] single nucleotide polymorphisms with diastolic blood pressure (DBP; β=0.28, P=2.47×10(-5)) and carotid intima-media thickness (cIMT; β=-0.0061, P=2.89×10(-5)). In summary, these results show that genomic instability and cellular senescence in VSMCs increase PDE1 expression. This might play a role in aging-related loss of vasodilator function, VSMC senescence, increased blood pressure and vascular hypertrophy. 
|mesh-terms=* Aging
* Animals
* Blood Pressure
* Carotid Arteries
* Carotid Artery Diseases
* Carotid Intima-Media Thickness
* Cells, Cultured
* Cellular Senescence
* Cyclic GMP
* Cyclic Nucleotide Phosphodiesterases, Type 1
* Cyclic Nucleotide Phosphodiesterases, Type 5
* DNA-Binding Proteins
* Dose-Response Relationship, Drug
* Endonucleases
* Gene Expression Regulation, Neoplastic
* Genetic Predisposition to Disease
* Genome-Wide Association Study
* Humans
* Hydrolysis
* Hyperplasia
* Hypertension
* In Vitro Techniques
* Mice, Inbred C57BL
* Mice, Knockout
* Muscle, Smooth, Vascular
* Myocytes, Smooth Muscle
* Phenotype
* Phosphodiesterase 5 Inhibitors
* Polymorphism, Single Nucleotide
* Second Messenger Systems
* Vasodilation
* Vasodilator Agents
|keywords=* aging
* blood pressure
* genetic association
* phosphodiesterases
* vascular disease
|full-text-url=https://sci-hub.do/10.1042/CS20140753
}}
{{medline-entry
|title=Cyclic nucleotide phosphodiesterase 1 and vascular aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26374857
|abstract=VSMCs (vascular smooth muscle cells) play critical roles in arterial remodelling with aging, hypertension and atherosclerosis. VSMCs exist in diverse phenotypes and exhibit phenotypic plasticity, e.g. changing from a quiescent/contractile phenotype to an active myofibroblast-like, often called 'synthetic', phenotype. Synthetic VSMCs are able to proliferate, migrate and secrete ECM (extracellular matrix) proteinases and ECM proteins. In addition, they produce pro-inflammatory molecules, providing an inflammatory microenvironment for leucocyte penetration, accumulation and activation. The aging VSMCs have also shown changes in cellular phenotype, responsiveness to contracting and relaxing mediators, replicating potential, matrix synthesis, inflammatory mediators and intracellular signalling. VSMC dysfunction plays a key role in age-associated vascular remodelling. Cyclic nucleotide PDEs (phosphodiesterases), by catalysing cyclic nucleotide hydrolysis, play a critical role in regulating the amplitude, duration and compartmentalization of cyclic nucleotide signalling. Abnormal alterations of PDEs and subsequent changes in cyclic nucleotide homoeostasis have been implicated in a number of different diseases. In the study published in the latest issue of Clinical Science, Bautista Niño and colleagues have shown that, in cultured senescent human VSMCs, [[PDE1A]] and [[PDE1C]] mRNA levels are significantly up-regulated and inhibition of PDE1 activity with vinpocetine reduced cellular senescent makers in senescent VSMCs. Moreover, in the premature aging mice with genomic instability (Ercc1(d/-)), impaired aortic ring relaxation in response to SNP (sodium nitroprusside), an NO (nitric oxide) donor, was also largely improved by vinpocetine. More interestingly, using data from human GWAS (genome-wide association studies), it has been found that [[PDE1A]] single nucleotide polymorphisms is significantly associated with diastolic blood pressure and carotid intima-media thickening, two hallmarks of human vascular dysfunction in aging. These findings establish a strong relationship between PDE1 expression regulation and vascular abnormalities in aging. 
|mesh-terms=* Aging
* Animals
* Cyclic Nucleotide Phosphodiesterases, Type 1
* Humans
* Muscle, Smooth, Vascular
* Myocytes, Smooth Muscle
* Vasodilation
|keywords=* aging
* cyclic nucleotide phosphodiesterase
* extracellular matrix
* genome-wide association study
* intima–media thickening
* vascular smooth muscle cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610264
}}
{{medline-entry
|title=Select 3',5'-cyclic nucleotide phosphodiesterases exhibit altered expression in the aged rodent brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24184653
|abstract=3',5'-cyclic nucleotide phosphodiesterases (PDEs) are the only known enzymes to compartmentalize cAMP and cGMP, yet little is known about how PDEs are dynamically regulated across the lifespan. We mapped mRNA expression of all 21 PDE isoforms in the adult rat and mouse central nervous system (CNS) using quantitative polymerase chain reaction (qPCR) and in situ hybridization to assess conservation across species. We also compared PDE mRNA and protein in the brains of old (26 months) versus young (5 months) Sprague-Dawley rats, with select experiments replicated in old (9 months) versus young (2 months) BALB/cJ mice. We show that each PDE isoform exhibits a unique expression pattern across the brain that is highly conserved between rats, mice, and humans. [[PDE1B]], [[PDE1C]], [[PDE2A]], [[PDE4A]], [[PDE4D]], [[PDE5A]], [[PDE7A]], [[PDE8A]], [[PDE8B]], [[PDE10A]], and [[PDE11A]] showed an age-related increase or decrease in mRNA expression in at least 1 of the 4 brain regions examined (hippocampus, cortex, striatum, and cerebellum). In contrast, mRNA expression of [[PDE1A]], [[PDE3A]], [[PDE3B]], [[PDE4B]], [[PDE7A]], [[PDE7B]], and [[PDE9A]] did not change with age. Age-related increases in [[PDE11A]]4, [[PDE8A]]3, [[PDE8A]]4/5, and [[PDE1C]]1 protein expression were confirmed in hippocampus of old versus young rodents, as were age-related increases in [[PDE8A]]3 protein expression in the striatum. Age-related changes in PDE expression appear to have functional consequences as, relative to young rats, the hippocampi of old rats demonstrated strikingly decreased phosphorylation of GluR1, CaMKIIα, and CaMKIIβ, decreased expression of the transmembrane AMPA regulatory proteins γ2 (a.k.a. stargazin) and γ8, and increased trimethylation of H3K27. Interestingly, expression of [[PDE11A]]4, [[PDE8A]]4/5, [[PDE8A]]3, and [[PDE1C]]1 correlate with these functional endpoints in young but not old rats, suggesting that aging is not only associated with a change in PDE expression but also a change in PDE compartmentalization.
|mesh-terms=* 3',5'-Cyclic-AMP Phosphodiesterases
* Aging
* Animals
* Brain
* Cerebellum
* Cerebral Cortex
* Corpus Striatum
* Gene Expression Regulation, Enzymologic
* Hippocampus
* Male
* Mice
* Mice, Inbred BALB C
* Protein Isoforms
* RNA, Messenger
* Rats
* Rats, Sprague-Dawley
|keywords=* Alzheimer's disease
* Model
* Neuron
* PDE11
* PDE8
* Tissue distribution
|full-text-url=https://sci-hub.do/10.1016/j.cellsig.2013.10.007
}}