Differential Regulation of Human Platelet Responses by cGMP Inhibited and Stimulated cAMP Phosphodiesterases

Manns, Joanne M.; Brennan, Kathleen; Colman, R. W.; Sheth, S. B.

doi:10.1055/s-0037-1613099

Cited by 43 publications

(30 citation statements)

References 28 publications

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“…The miRNAs hsa-miR-582-5P and hsa-miR-139-3p are located within PDE4D and PDE2A loci respectively; both genes participate in cAMP regulation. [35][36][37] The fifth intron of the mannose receptor MRC1 contains hsa-miR-511; this gene is involved in NFjB signalling. 38 Gene GCP1 contains hsa-miR-149, one of the two microRNA species that showed a significant association with pericellular fibrosis, and is linked to FGF and TGFb signal transduction.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of miRNAs in the visceral adipose tissue of patients with non‐alcoholic fatty liver disease

Estep

Armistead

Hossain

et al. 2010

Aliment Pharmacol Ther

126

115

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Aliment Pharmacol Ther 2010; 32: 487–497SummaryBackground Progression of non‐alcoholic fatty liver disease (NAFLD) can be facilitated by soluble molecules secreted by visceral adipose tissue (VAT). MicroRNAs (miRNAs) are likely to regulate some of these molecular pathways involved in pathogenesis of NAFLD.Aim To profile miRNA expression in the visceral adipose tissue of patients with NAFLD.Methods Visceral adipose tissue samples were collected from NAFLD patients and frozen. Patients with biopsy‐proven NAFLD were divided into non‐alcoholic steatohepatitis (NASH) (n = 12) and non‐NASH (n = 12) cohorts controlled for clinical and demographic characteristics. Extracted total RNA was profiled using TaqMan Human MicroRNA arrays. Univariate Mann–Whitney comparisons and multivariate regression analysis were performed to compare miRNA profiles.Results A total of 113 miRNA differentially expressed between NASH patients and non‐NASH patients (P < 0.05). Of these, seven remained significant after multiple test correction (hsa‐miR‐132, hsa‐miR‐150, hsa‐miR‐433, hsa‐miR‐28‐3p, hsa‐miR‐511, hsa‐miR‐517a, hsa‐miR‐671). Predicted target genes for these miRNAs include insulin receptor pathway components (IGF1, IGFR13), cytokines (CCL3, IL6), ghrelin/obestatin gene, and inflammation‐related genes (NFKB1, RELB, FAS). In addition, two miRNA species, hsa‐miR‐197 and hsa‐miR‐99, were significantly associated with pericellular fibrosis in NASH patients (P < 0.05). Levels of IL‐6 in the serum negatively correlated with the expression levels of all seven miRNAs capable of down regulating IL‐6 encoding gene.Conclusions miRNA expression from VAT may contribute to the pathogenesis of NAFLD – a finding which may distinguish relatively simple steatosis from NASH. This could help identify potential targets for pharmacological treatment regimens and candidate biomarkers for NASH.

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Section: Discussionmentioning

confidence: 99%

Differential expression of miRNAs in the visceral adipose tissue of patients with non‐alcoholic fatty liver disease

Estep

Armistead

Hossain

et al. 2010

Aliment Pharmacol Ther

126

115

View full text Add to dashboard Cite

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“…5 To determine whether the increase of total cAMP-PDE activity stimulated by thrombin was due to PDE2A, PDE3A, or both, we applied a variety of PDE inhibitors, including a nonselective inhibitor and selective PDE2 or PDE3 inhibitors. When the platelets were treated with the nonselective PDE inhibitor IBMX at 10 mol/L (Figure 2), thrombin increased cAMP-PDE activity only 4% compared with its own control.…”

Section: Activation Of Pde3a By Thrombin and A Par-1 Agonistmentioning

confidence: 99%

Thrombin regulates intracellular cyclic AMP concentration in human platelets through phosphorylation/activation of phosphodiesterase 3A

Zhang

Colman

2007

Blood

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Thrombin-induced cyclic AMP (cAMP) reduction potentates several steps in platelet activation, including Ca ؉؉ mobilization, cytoskeletal reorganization, and fibrinogen receptor conformation. We now reinvestigate the signaling pathways by which intracellular cAMP content is controlled after platelet activation by thrombin. When washed human platelets were stimulated with thrombin, cAMPdependent phosphodiesterase (PDE3A) activity was significantly increased. A nonselective PDE inhibitor, 3-isobutyl-1-methylxanthine (IBMX), and the PDE3 selective inhibitors milrinone and cilostazol each suppressed thrombin-induced cAMP-dependent PDE responses, but not 2 different PDE2 inhibitors. Selective inhibition of PDE3A resulted in reversal of thrombin-induced cAMP reduction, indicating that thrombin activated PDE3A. In synergy with inhibition of adenylate cyclase by thrombin, activated PDE3A accelerates cAMP hydrolysis and maximally reduces the cAMP content. Thrombininduced PDE3A activation was diminished concomitantly with dephosphorylation of PDE3A by protein phosphatase 1 (PP1). An Akt inhibitor blocked PDE3A activation and constrained thrombininduced cAMP reduction. A P2Y 12 inhibitor also reduced thrombin-induced cAMP reduction. The combination of both reversed cAMP decrease by thrombin. Thrombin-mediated phosphorylated PDE3A was isolated by liquid chromatography, detected by a monoclonal antibody against Akt-phosphorylated substrate, and verified by immunoprecipitation study. The predominant isoform phosphorylated by Akt was the 136-kDa species. We suggest that activation/ phosphorylation of PDE3A via Akt signaling pathway participates in regulating cAMP during thrombin activation of platelets.

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“…Protein kinase C contributes to platelet activation both directly, through affinity regulation of the fibrinogen receptor, integrin ␣ IIb ␤ 3 (1), and indirectly by enhancing degranulation (2). Thrombin also stimulates activation of PI 3-kinases and subsequent generation of PI (3,4,5) trisphosphate and PI (3,4) bisphosphate (3), which recruit protein kinase B (PKB) to the plasma membrane where it becomes phosphorylated and activated.…”

mentioning

confidence: 99%

Protein Kinase C-mediated Phosphorylation and Activation of PDE3A Regulate cAMP Levels in Human Platelets

Hunter

MacKintosh

Hers

2009

Journal of Biological Chemistry

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The elevation of [cAMP] i is an important mechanism of platelet inhibition and is regulated by the opposing activity of adenylyl cyclase and phosphodiesterase (PDE). In this study, we demonstrate that a variety of platelet agonists, including thrombin, significantly enhance the activity of PDE3A in a phosphorylation-dependent manner. Upon vascular injury, platelets adhere to the newly exposed subintimal collagen and undergo activation leading to platelet spreading to cover the damaged region and release of thrombogenic factors such as ADP and thromboxane A 2 . In addition, platelets are activated by thrombin, which is generated as a result of activation of the coagulation pathway, and stimulates platelets by cleaving the protease-activated receptors (PAR), 2 PAR-1 and PAR-4. The final common pathway is the exposure of fibrinogen binding sites on integrin ␣ IIb ␤ 3 resulting in platelet aggregation and thrombus formation.Thrombin-mediated cleavage of PARs leads to activation of phospholipase C ␤ (PLC), hydrolysis of phosphatidylinositol (PI) 4,5-bisphosphate and a subsequent increase in [Ca 2ϩ ] i and activation of protein kinase C (PKC). Protein kinase C contributes to platelet activation both directly, through affinity regulation of the fibrinogen receptor, integrin ␣ IIb ␤ 3 (1), and indirectly by enhancing degranulation (2). Thrombin also stimulates activation of PI 3-kinases and subsequent generation of PI (3, 4, 5) trisphosphate and PI (3, 4) bisphosphate (3), which recruit protein kinase B (PKB) to the plasma membrane where it becomes phosphorylated and activated.Platelet activation is opposed by agents that raise intracellular 3Ј-5Ј-cyclic adenosine monophosphate ([cAMP] i ). cAMP is a powerful inhibitory second messenger that down-regulates platelet function by interfering with Ca 2ϩ homeostasis, degranulation and integrin activation (4). Synthesis of cAMP is stimulated by mediators such as prostaglandin I 2 (PGI 2 ), which bind to G s -coupled receptors leading to activation of adenylate cyclase (AC). This inhibitory pathway is opposed by thrombin, which inhibits the elevation of cAMP indirectly via autocrine activation of the G i -coupled ADP receptor P2Y 12 . cAMP signaling is terminated by hydrolysis to biologically inert 5Ј-AMP by 3Ј-phosphodiesterases. Platelets express two cAMP phosphodiesterase isoforms, cGMP-stimulated PDE2 and cGMP-inhibited PDE3A. PDE3A is the most abundant isoform in platelets and has a ϳ250-fold lower K m for cAMP than PDE2 (4). As a consequence of these properties, PDE3A exerts a greater influence on cAMP homeostasis, particularly at resting levels. The importance of PDE3A in platelet function is further emphasized by the finding that the PDE3A inhibitors cilostamide and milrinone raise basal cAMP levels and strongly inhibit thrombin-induced platelet activation (5). Furthermore, PDE3A

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Differential Regulation of Human Platelet Responses by cGMP Inhibited and Stimulated cAMP Phosphodiesterases

Cited by 43 publications

References 28 publications

Differential expression of miRNAs in the visceral adipose tissue of patients with non‐alcoholic fatty liver disease

Differential expression of miRNAs in the visceral adipose tissue of patients with non‐alcoholic fatty liver disease

Thrombin regulates intracellular cyclic AMP concentration in human platelets through phosphorylation/activation of phosphodiesterase 3A

Protein Kinase C-mediated Phosphorylation and Activation of PDE3A Regulate cAMP Levels in Human Platelets

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