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Cyclic nucleotide phosphodiesterases (PDEs) and endothelial function in ischaemic stroke. A review.

Yasmeen, S; Akram, BH; Hainsworth, AH; Kruuse, C (2019) Cyclic nucleotide phosphodiesterases (PDEs) and endothelial function in ischaemic stroke. A review. Cell Signal, 61. pp. 108-119. ISSN 1873-3913 https://doi.org/10.1016/j.cellsig.2019.05.011
SGUL Authors: Hainsworth, Atticus Henry

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Abstract

BACKGROUND: Endothelial dysfunction is a hallmark of cerebrovascular disease, including ischemic stroke. Modulating endothelial signalling by cyclic nucleotides, cAMP and cGMP, is a potential therapeutic target in stroke. Inhibitors of the cyclic nucleotide degrading phosphodiesterase (PDE) enzymes may restore cerebral endothelial function. Current knowledge on PDE distribution and function in cerebral endothelial cells is sparse. This review explores data on PDE distribution and effects of PDEi in cerebral endothelial cells and identifies which PDEs are potential treatment targets in stroke. METHOD: We performed a systematic search of electronic databases (Medline and Embase). Our search terms were cerebral ischaemia, cerebral endothelial cells, cyclic nucleotide, phosphodiesterase and phosphodiesterase inhibitors. RESULTS: We found 23 publications which described effects of selective inhibitors of only three PDE families on endothelial function in ischemic stroke. PDE3 inhibitors (PDE3i) (11 publications) and PDE4 inhibitors (PDE4i) (3 publications) showed anti-inflammatory, anti-apoptotic or pro-angiogenic effects. PDE3i also reduced leucocyte infiltration and MMP-9 expression. Both PDE3i and PDE4i increased expression of tight junction proteins and protected the blood-brain barrier. PDE5 inhibitors (PDE5i) (6 publications) reduced inflammation and apoptosis. In preclinical models, PDE5i enhanced cGMP/NO signalling associated with microvascular angiogenesis, increased cerebral blood flow and improved functional recovery. Non-specific PDEi (3 publications) had mainly anti-inflammatory effects. CONCLUSION: This review demonstrates that non-selective and selective PDEi of PDE3, PDE4 and PDE5 modulated endothelial function in cerebral ischemic stroke by regulating processes involved in vascular repair and neuroprotection and thus reduced cell death and inflammation. Of note, they promoted angiogenesis, microcirculation and improved functional recovery; all are important in stroke prevention and recovery, and effects should be further evaluated in humans.

Item Type: Article
Additional Information: © 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: Cyclic nucleotide, Endothelial function, PDE, Stroke, cAMP, cGMP, 0601 Biochemistry And Cell Biology, Biochemistry & Molecular Biology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Cell Signal
ISSN: 1873-3913
Language: eng
Dates:
DateEvent
September 2019Published
24 May 2019Published Online
22 May 2019Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Projects:
Project IDFunderFunder ID
UNSPECIFIEDHerlev Research CouncilUNSPECIFIED
UNSPECIFIEDNovo Nordic FoundationUNSPECIFIED
PubMed ID: 31132399
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/110911
Publisher's version: https://doi.org/10.1016/j.cellsig.2019.05.011

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