PDE-Mediated Cyclic Nucleotide Compartmentation in Vascular Smooth Muscle Cells: From Basic to a Clinical Perspective

Oliveira, Nelson Fernandes de; Cairrão, Elisa

doi:10.3390/jcdd9010004

Cited by 14 publications

(7 citation statements)

References 271 publications

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“…Moreover, a mutated PDE3A gene drives mechanisms increasing the peripheral vascular resistance which may lead to hypertension. 16 With the development of hypertension in conditions of salt load in the serum increases the content of aldosterone, accompanied by an increase in blood pressure. 33 Therefore, interest in the activity of PDE in studies on the model of salt hypertension is also due to the participation of this enzyme in the regulation of aldosterone secretion in the glomerular zone of the kidneys against the background of reduced intracellular cAMP.…”

Section: Resultsmentioning

confidence: 99%

“… 14 It should be noted that this fragment is unique to the PDE3 family and is considered a key factor in determining the structure of enzyme inhibitors. 15 , 16 The structure of the catalytic domain of PDE3 is presented in Figure 1 . The structure of the catalytic domain PDE3B consists of three subdomains ( Figure 1A ) 17 : N-terminal subdomain (light brown), linker subdomain (light green), C-terminal subdomain (purple).…”

Section: Introductionmentioning

confidence: 99%

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New Prospective Phosphodiesterase Inhibitors: Phosphorylated Oxazole Derivatives in Treatment of Hypertension

et al. 2022

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One of the promising chemical groups for the development of new antihypertensive medicines, the action of which is associated with the inhibition of phosphodiesterase III (PDE3) activity, are phosphorylated oxazole derivatives (OVPs). Purpose: To prove experimentally the presence of the OVPs antihypertensive effect associated with decreasing of PDE activity and to justify its molecular mechanism. Methods: An experimental study of the effect of OVPs on phosphodiesterase activity was performed on Wistar rats. Determination of PDE activity was performed by fluorimetric method using umbelliferon in blood serum and organs. The docking method was used to investigate the potential molecular mechanisms of the antihypertensive action of OVPs with PDE3. Results: The introduction of OVP-1 50 mg/kg, as a leader compound, led to the restoration of PDE activity in the aorta, heart and serum of rats with hypertension to the values observed in the intact group. This may indicate the possibility of the development of vasodilating action of OVPs by the influence of the latter on the increase in cGMP synthesis due to inhibition of PDE activity. The calculated results of molecular docking of ligands OVPs to the active site of PDE3 showed that all test compounds have a common type of complexation due to phosphonate groups, piperidine rings, side and terminal phenyl and methylphenyl groups. Conclusion: The analysis of the obtained results both in vivo and in silico showed that phosphorylated oxazole derivatives represent a new platform for further studies as phosphodiesterase III inhibitors with antihypertensive activity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

New Prospective Phosphodiesterase Inhibitors: Phosphorylated Oxazole Derivatives in Treatment of Hypertension

et al. 2022

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“…PDE-mediated compartmentation plays a significant role in cAMP/cGMP signaling in different cell types. In smooth muscle cells [ 111 ] and cardiac myocytes [ 112 , 113 ] cAMP/cGMP concentration is tightly regulated in different compartments (microdomains), which is important for the precise spatial and temporal control of cyclic nucleotide signaling in these cells. The question of whether similar mechanisms of cyclic nucleotide compartmentalization are also present in platelets remains open, and merits future experimental confirmations.…”

Section: Nitrate/nitrite/no Pathwaymentioning

confidence: 99%

The Role of NO/sGC/cGMP/PKG Signaling Pathway in Regulation of Platelet Function

Gambaryan

2022

Cells

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Circulating blood platelets are controlled by stimulatory and inhibitory factors, and a tightly regulated equilibrium between these two opposing processes is essential for normal platelet and vascular function. NO/cGMP/ Protein Kinase G (PKG) pathways play a highly significant role in platelet inhibition, which is supported by a large body of studies and data. This review focused on inconsistent and controversial data of NO/sGC/cGMP/PKG signaling in platelets including sources of NO that activate sGC in platelets, the role of sGC/PKG in platelet inhibition/activation, and the complexity of the regulation of platelet inhibitory mechanisms by cGMP/PKG pathways. In conclusion, we suggest that the recently developed quantitative phosphoproteomic method will be a powerful tool for the analysis of PKG-mediated effects. Analysis of phosphoproteins in PKG-activated platelets will reveal many new PKG substrates. A future detailed analysis of these substrates and their involvement in different platelet inhibitory pathways could be a basis for the development of new antiplatelet drugs that may target only specific aspects of platelet functions.

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“…Half of N-terminal region of the protein regulates PDE enzymatic activity and subcellular localization. Protein kinases targeting phosphorylation sites and lipid modification sites are present in some PDEs ( Omori and Kotera, 2007 ; Lorigo et al, 2022 ).…”

Section: Phosphodiesterases and Their Inhibitorsmentioning

confidence: 99%

Inhibition of phosphodiesterase: A novel therapeutic target for the treatment of mild cognitive impairment and Alzheimer’s disease

Sheng¹,

Zhang²,

Wu³

et al. 2022

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is the most common form of dementia and is ranked as the 6th leading cause of death in the US. The prevalence of AD and dementia is steadily increasing and expected cases in USA is 14.8 million by 2050. Neuroinflammation and gradual neurodegeneration occurs in Alzheimer’s disease. However, existing medications has limitation to completely abolish, delay, or prevent disease progression. Phosphodiesterases (PDEs) are large family of enzymes to hydrolyze the 3’-phosphodiester links in cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in signal-transduction pathways for generation of 5’-cyclic nucleotides. It plays vital role to orchestrate several pharmacological activities for proper cell functioning and regulating the levels of cAMP and cGMP. Several evidence has suggested that abnormal cAMP signaling is linked to cognitive problems in neurodegenerative disorders like AD. Therefore, the PDE family has become a widely accepted and multipotential therapeutic target for neurodegenerative diseases. Notably, modulation of cAMP/cGMP by phytonutrients has a huge potential for the management of AD. Natural compounds have been known to inhibit phosphodiesterase by targeting key enzymes of cGMP synthesis pathway, however, the mechanism of action and their therapeutic efficacy has not been explored extensively. Currently, few PDE inhibitors such as Vinpocetine and Nicergoline have been used for treatment of central nervous system (CNS) disorders. Considering the role of flavonoids to inhibit PDE, this review discussed the therapeutic potential of natural compounds with PDE inhibitory activity for the treatment of AD and related dementia.

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PDE-Mediated Cyclic Nucleotide Compartmentation in Vascular Smooth Muscle Cells: From Basic to a Clinical Perspective

Cited by 14 publications

References 271 publications

New Prospective Phosphodiesterase Inhibitors: Phosphorylated Oxazole Derivatives in Treatment of Hypertension

New Prospective Phosphodiesterase Inhibitors: Phosphorylated Oxazole Derivatives in Treatment of Hypertension

The Role of NO/sGC/cGMP/PKG Signaling Pathway in Regulation of Platelet Function

Inhibition of phosphodiesterase: A novel therapeutic target for the treatment of mild cognitive impairment and Alzheimer’s disease

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