The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Joanna M Wardlaw - One of the best experts on this subject based on the ideXlab platform.

  • cilostazol for secondary prevention of stroke and cognitive decline systematic review and meta analysis
    Stroke, 2020
    Co-Authors: Caroline A Mchutchison, Philip M.w. Bath, Gordon W Blair, Jason P Appleton, Francesca M Chappell, Fergus N Doubal, Joanna M Wardlaw
    Abstract:

    Background and Purpose: Cilostazol, a Phosphodiesterase 3’ inhibitor, is used in Asia-Pacific countries for stroke prevention, but rarely used elsewhere. In addition to weak antiplatelet effects, i...

  • pharmacological treatment and prevention of cerebral small vessel disease a review of potential interventions
    International Journal of Stroke, 2015
    Co-Authors: Philip M.w. Bath, Joanna M Wardlaw
    Abstract:

    Small vessel disease encompasses lacunar stroke, white matter hyperintensities, lacunes and microbleeds. It causes a quarter of all ischemic strokes, is the commonest cause of vascular dementia, and the cause is incompletely understood. Vascular prophylaxis, as appropriate for large artery disease and cardioembolism, includes antithrombotics, and blood pressure and lipid lowering; however, these strategies may not be effective for small vessel disease, or are already used routinely so precluding further detailed study. Further, intensive antiplatelet therapy is known to be hazardous in small vessel disease through enhanced bleeding. Whether acetylcholinesterase inhibitors, which delay the progression of Alzheimer's dementia, are relevant in small vessel disease remains unclear. Potential prophylactic and treatment strategies might be those that target brain microvascular endothelium and the blood brain barrier, microvascular function and neuroinflammation. Potential interventions include endothelin antagonists, neurotrophins, nitric oxide donors and Phosphodiesterase 5 inhibitors, peroxisome proliferator-activated receptor-gamma agonists, and prostacyclin mimics and Phosphodiesterase 3 inhibitors. Several drugs that have relevant properties are licensed for other disorders, offering the possibility of drug repurposing. Others are in development. Since influencing multiple targets may be most effective, using multiple agents and/or those that have multiple effects may be preferable. We focus on potential small vessel disease mechanistic targets, summarize drugs that have relevant actions, and review data available from randomized trials on their actions and on the available evidence for their use in lacunar stroke.

Maria Gabriella Matera - One of the best experts on this subject based on the ideXlab platform.

  • effect of the mixed Phosphodiesterase 3 4 inhibitor rpl554 on human isolated bronchial smooth muscle tone
    Journal of Pharmacology and Experimental Therapeutics, 2013
    Co-Authors: Luigino Calzetta, Clive P Page, Domenico Spina, Mario Cazzola, Paola Rogliani, Francesco Facciolo, Maria Gabriella Matera
    Abstract:

    The Phosphodiesterase (PDE) enzyme family hydrolyzes cAMP and cGMP, second messengers that regulate a variety of cellular processes, including airway smooth muscle (ASM) relaxation and the inhibition of inflammatory cells. We investigated the activity of RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-( n -carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2 H -pyrimido[6,1- a ]isoquinolin-4-one], a dual PDE3/PDE4 inhibitor that exhibits bifunctional activity for its effects on the tone of human isolated ASM and any potential synergistic interactions with muscarinic receptor antagonists or a β 2 -agonist. We evaluated the influence of RPL554 on the contractile response induced by electrical field stimulation (EFS), acetylcholine (ACh), or histamine on human isolated bronchi. We also analyzed the potential synergistic effect of RPL554 in combination with atropine, glycopyrollate, or salbutamol by using the Berenbaum Bliss Independence (BI), or the dose equivalence methods. RPL554 inhibited the contraction induced by EFS [maximal effectiveness ( E max ) 91.33 ± 3.37%, P E max 94.62 ± 2.63%, p D 2 4.84 ± 0.12, P

  • effect of the mixed Phosphodiesterase 3 4 inhibitor rpl554 on human isolated bronchial smooth muscle tone
    Journal of Pharmacology and Experimental Therapeutics, 2013
    Co-Authors: Luigino Calzetta, Clive P Page, Domenico Spina, Mario Cazzola, Paola Rogliani, Francesco Facciolo, Maria Gabriella Matera
    Abstract:

    The Phosphodiesterase (PDE) enzyme family hydrolyzes cAMP and cGMP, second messengers that regulate a variety of cellular processes, including airway smooth muscle (ASM) relaxation and the inhibition of inflammatory cells. We investigated the activity of RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-( n -carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2 H -pyrimido[6,1- a ]isoquinolin-4-one], a dual PDE3/PDE4 inhibitor that exhibits bifunctional activity for its effects on the tone of human isolated ASM and any potential synergistic interactions with muscarinic receptor antagonists or a β 2 -agonist. We evaluated the influence of RPL554 on the contractile response induced by electrical field stimulation (EFS), acetylcholine (ACh), or histamine on human isolated bronchi. We also analyzed the potential synergistic effect of RPL554 in combination with atropine, glycopyrollate, or salbutamol by using the Berenbaum Bliss Independence (BI), or the dose equivalence methods. RPL554 inhibited the contraction induced by EFS [maximal effectiveness ( E max ) 91.33 ± 3.37%, P E max 94.62 ± 2.63%, p D 2 4.84 ± 0.12, P

D Alvarezhernandez - One of the best experts on this subject based on the ideXlab platform.

  • vascular smooth muscle cell calcification is mediated by regulated exosome secretion
    Circulation Research, 2015
    Co-Authors: Alexander N Kapustin, Ying Zheng, Martijn L Chatrou, Ignat Drozdov, Sean M Davidson, Daniel Soong, Malgorzata Furmanik, P Sanchis, Rafael Torres Martin De Rosales, D Alvarezhernandez
    Abstract:

    Rationale: Matrix vesicles (MVs), secreted by vascular smooth muscle cells (VSMCs), form the first nidus for mineralization and fetuin-A, a potent circulating inhibitor of calcification, is specifically loaded into MVs. However, the processes of fetuin-A intracellular trafficking and MV biogenesis are poorly understood. Objective: The objective of this study is to investigate the regulation, and role, of MV biogenesis in VSMC calcification. Methods and Results: Alexa488-labeled fetuin-A was internalized by human VSMCs, trafficked via the endosomal system, and exocytosed from multivesicular bodies via exosome release. VSMC-derived exosomes were enriched with the tetraspanins CD9, CD63, and CD81, and their release was regulated by sphingomyelin Phosphodiesterase 3. Comparative proteomics showed that VSMC-derived exosomes were compositionally similar to exosomes from other cell sources but also shared components with osteoblast-derived MVs including calcium-binding and extracellular matrix proteins. Elevated extracellular calcium was found to induce sphingomyelin Phosphodiesterase 3 expression and the secretion of calcifying exosomes from VSMCs in vitro, and chemical inhibition of sphingomyelin Phosphodiesterase 3 prevented VSMC calcification. In vivo, multivesicular bodies containing exosomes were observed in vessels from chronic kidney disease patients on dialysis, and CD63 was found to colocalize with calcification. Importantly, factors such as tumor necrosis factor-α and platelet derived growth factor-BB were also found to increase exosome production, leading to increased calcification of VSMCs in response to calcifying conditions. Conclusions: This study identifies MVs as exosomes and shows that factors that can increase exosome release can promote vascular calcification in response to environmental calcium stress. Modulation of the exosome release pathway may be as a novel therapeutic target for prevention.

Chen Yan - One of the best experts on this subject based on the ideXlab platform.

  • role of Phosphodiesterase 3 in no cgmp mediated antiinflammatory effects in vascular smooth muscle cells
    Circulation Research, 2003
    Co-Authors: Toru Aizawa, Jun Ichi Abe, Heng Wei, Bradford C. Berk, Joseph M Miano, Chen Yan
    Abstract:

    Atherosclerosis involves cellular immune responses and altered vascular smooth muscle cell (VSMC) function. Nitric oxide (NO)/cGMP is uniquely capable of inhibiting key processes in atherosclerosis. In this study, we determined the effects of NO/cGMP and their molecular mechanisms in the regulation of NF-kappaB-dependent gene expression in VSMCs. We found that cGMP-elevating agents such as the NO donor S-nitroso-N-acetylpenicillamine (SNAP) and C-type natriuretic peptide (CNP), reduced TNF-alpha-induced NF-kappaB-dependent reporter gene expression in rat aortic VSMCs in a cGMP-dependent manner. The effects of SNAP and CNP on NF-kappaB are mediated by cAMP-dependent protein kinase (PKA) but not cGMP-dependent protein kinase (PKG) based on the findings that the selective PKA inhibitor, PKI, abolished the effects of SNAP and CNP on NF-kappaB, whereas the PKG inhibitor Rp-8-Br-PET-cGMP had no effect. Inhibition of cGMP-inhibited cAMP-hydrolyzing Phosphodiesterase 3 (PDE3) blocked SNAP- and CNP-elicited effects on NF-kappaB-dependent transcription. Furthermore, cGMP analogues such as 8-pCPT-cGMP, which selectively activates PKG but does not inhibit PDE3, had no effect on NF-kappaB-mediated transcription. Activation of PKA by SNAP or cAMP-elevating agents not only inhibited TNF-alpha-induced NF-kappaB-dependent reporter gene expression but also reduced endogenous NF-kappaB-dependent adhesion molecule and chemokine expression. These results suggest that SNAP and CNP exert inhibitory effects on NF-kappaB-dependent transcription by activation of PKA via cGMP-dependent inhibition of PDE3 activity. Therefore, PDE3 is a novel mediator of inflammation in VSMCs.

Toru Aizawa - One of the best experts on this subject based on the ideXlab platform.

  • a positive feedback loop of Phosphodiesterase 3 pde3 and inducible camp early repressor icer leads to cardiomyocyte apoptosis
    Proceedings of the National Academy of Sciences of the United States of America, 2005
    Co-Authors: Bo Ding, Jun Ichi Abe, Heng Wei, Carlos A. Molina, Junichi Sadoshima, Burns C. Blaxall, Toru Aizawa, Wenyi Che, Weimin Liu, Bradford C. Berk
    Abstract:

    cAMP plays crucial roles in cardiac remodeling and the progression of heart failure. Recently, we found that expression of cAMP hydrolyzing Phosphodiesterase 3A (PDE3A) was significantly reduced in human failing hearts, accompanied by up-regulation of inducible cAMP early repressor (ICER) expression. Angiotensin II (Ang II) and the β-adrenergic receptor agonist isoproterenol (ISO) also induced persistent PDE3A down-regulation and concomitant ICER up-regulation in vitro, which is important in Ang II- and ISO-induced cardiomyocyte apoptosis. We hypothesized that interactions between PDE3A and ICER may constitute an autoregulatory positive feedback loop (PDE3A-ICER feedback loop), and this loop would cause persistent PDE3A down-regulation and ICER up-regulation. Here, we demonstrate that ICER induction repressed PDE3A gene transcription. PDE3A down-regulation activated cAMP/PKA signaling, leading to ICER up-regulation via PKA-dependent stabilization of ICER. With respect to Ang II, the initiation of the PDE3A-ICER feedback loop depends on activation of Ang II type 1 receptor (AT1R), classical PKC(s), and CREB (cAMP response element binding protein). We further show that the PDE3A-ICER feedback loop is essential for Ang II-induced cardiomyocyte apoptosis. ISO and PDE3 inhibitors also induced the PDE3A-ICER feedback loop and subsequent cardiomyocyte apoptosis, highlighting the importance of this PDE3A-ICER feedback loop and cAMP signaling in cardiomyocyte apoptosis. Our findings may provide a therapeutic paradigm to prevent cardiomyocyte apoptosis and the progression of heart failure by inhibiting the PDE3A-ICER feedback loop.

  • role of Phosphodiesterase 3 in no cgmp mediated antiinflammatory effects in vascular smooth muscle cells
    Circulation Research, 2003
    Co-Authors: Toru Aizawa, Jun Ichi Abe, Heng Wei, Bradford C. Berk, Joseph M Miano, Chen Yan
    Abstract:

    Atherosclerosis involves cellular immune responses and altered vascular smooth muscle cell (VSMC) function. Nitric oxide (NO)/cGMP is uniquely capable of inhibiting key processes in atherosclerosis. In this study, we determined the effects of NO/cGMP and their molecular mechanisms in the regulation of NF-kappaB-dependent gene expression in VSMCs. We found that cGMP-elevating agents such as the NO donor S-nitroso-N-acetylpenicillamine (SNAP) and C-type natriuretic peptide (CNP), reduced TNF-alpha-induced NF-kappaB-dependent reporter gene expression in rat aortic VSMCs in a cGMP-dependent manner. The effects of SNAP and CNP on NF-kappaB are mediated by cAMP-dependent protein kinase (PKA) but not cGMP-dependent protein kinase (PKG) based on the findings that the selective PKA inhibitor, PKI, abolished the effects of SNAP and CNP on NF-kappaB, whereas the PKG inhibitor Rp-8-Br-PET-cGMP had no effect. Inhibition of cGMP-inhibited cAMP-hydrolyzing Phosphodiesterase 3 (PDE3) blocked SNAP- and CNP-elicited effects on NF-kappaB-dependent transcription. Furthermore, cGMP analogues such as 8-pCPT-cGMP, which selectively activates PKG but does not inhibit PDE3, had no effect on NF-kappaB-mediated transcription. Activation of PKA by SNAP or cAMP-elevating agents not only inhibited TNF-alpha-induced NF-kappaB-dependent reporter gene expression but also reduced endogenous NF-kappaB-dependent adhesion molecule and chemokine expression. These results suggest that SNAP and CNP exert inhibitory effects on NF-kappaB-dependent transcription by activation of PKA via cGMP-dependent inhibition of PDE3 activity. Therefore, PDE3 is a novel mediator of inflammation in VSMCs.