Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pulmonary fibroblast to myofibroblast conversion is a pathophysiological feature of idiopathic pulmonary fibrosis and COPD. This conversion is induced by transforming growth factor (TGF)-beta derived from epithelial cells as well as activated macrophages that have infiltrated the lung. Preventing this conversion might be a favourable therapeutic approach. Within this study we examined the activity of different members of the phosphodiesterase (PDE) family in primary human lung fibroblasts and various lung fibroblast cell lines both before and after TGF-beta induced differentiation to myofibroblasts as reflected by the expression of alpha-smooth muscle actin. We showed that the predominant PDE activities in lung fibroblasts are attributed to PDE5, PDE1 and to a smaller extent to PDE4. cyclic GMP (cGMP)-hydrolyzing activity declines by about half after differentiation to myofibroblasts in all pulmonary fibroblasts investigated, which is accompanied by a down-regulation of PDE5 protein. Lung fibroblast to myofibroblast differentiation is blocked by treatment with the PDE4 inhibitor piclamilast alone, depending on the TGF-beta concentration applied, and in combination with prostaglandin E(2) (PGE(2)) in a synergistic manner. Despite the high PDE5 activity the PDE5 inhibitor sildenafil by itself as well as in combination with brain natriuretic peptide or the nitric oxide-donor DETA-NONOate shows no inhibiting effects. However, combining sildenafil with the guanylyl cyclase (GC) activator BAY58-2667 and ODQ (which sensitizes GC for activation by BAY58-2667) suppressed TGF-beta induced differentiation. In summary, our data indicate that drugs interfering with the cyclic AMP (cAMP)-as well as with the NO-cGMP-pathway offer the therapeutic opportunity to prevent the differentiation of pulmonary fibroblasts to myofibroblasts in lung fibrosis.
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PMID:Inhibition of TGF-beta induced lung fibroblast to myofibroblast conversion by phosphodiesterase inhibiting drugs and activators of soluble guanylyl cyclase. 1765 76

The pulmonary vascular bed is both a source of and target for a number of vasoactive factors. Among the most important for pulmonary vascular homeostasis are factors that utilise cyclic guanosine monophosphate (cGMP) as an intracellular second messenger. These include nitric oxide and the natriuretic peptide family (atrial, brain and C-type natriuretic peptides). In the search for therapeutic strategies that engage the cGMP signalling pathway for the treatment of pulmonary arterial hypertension (PAH), inhibition of cGMP metabolism by phosphodiesterase type 5 (PDE5)-targeted compounds has proven most successful to date. One PDE5 inhibitor, sildenafil, has been shown to improve pulmonary haemodynamics and exercise capacity in patients with PAH and is now an approved treatment. Others are under investigation. An interesting, although still tentative, observation is the potential of sildenafil to reduce pulmonary vascular resistance without adversely affecting ventilation-perfusion matching. Another is the expression of phosphodiesterase type 5 in the hypertrophied right ventricle. These data suggest that phosphodiesterase type 5 inhibitors may have effects that distinguish them from other treatments for pulmonary hypertension and merit further study.
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PMID:Phosphodiesterase inhibitors for the treatment of pulmonary hypertension. 1859 37

Cyclic GMP-selective phosphodiesterase type 5 (PDE5) has been traditionally thought to play a little role in cardiac myocytes, yet recent studies using selective inhibitors such as sildenafil suggest it can potently modulate acute and chronic cardiac stress responses. To date, evidence for myocyte PDE5 expression and regulation has relied on small-molecule inhibitors and anti-sera, leaving open concerns regarding non-specific immune-reactivity, and off-target drug effects. To directly address both issues, we engineered a robust PDE5-gene silencing shRNA (inserted into miRNA-155 cassette) and DsRed-PDE5 fusion protein, both coupled to a CMV promoter and incorporated into adenoviral vectors. PDE5 mRNA and protein knock-down eliminated anti-sera positivity on immunoblots and fluorescent immuno-histochemistry in neonatal and adult cardiomyocytes, and suppressed PDE5 enzyme activity. Stimulation of myocyte hypertrophy by phenylephrine was blunted by PDE5 gene silencing in a protein kinase G dependent manner, and this effect was similar to that from sildenafil with no additive response by both combined. DsRed-PDE5 fusion protein expression showed normal z-band localization in adult myocytes but was diffused in eNOS(-/-) myocytes; echoing reported findings with anti-sera. PDE5 overexpression increased enzyme activity and amplified natriuretic peptide gene expression from phenylephrine stimulation. These data confirm PDE5 expression, activity, and targeted inhibition by sildenafil in cardiomyocytes, as well as the role of this PDE in cardiomyocyte hypertrophy modulation.
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PMID:Expression, activity, and pro-hypertrophic effects of PDE5A in cardiac myocytes. 1879 48

GPR35 is a Gi/o- and G16-coupled receptor abundantly expressed in gastrointestinal tissues and immune cells. Kynurenic acid (a tryptophan metabolite and ionotropic glutamate receptor antagonist) and zaprinast (a phosphodiesterase inhibitor) are GPR35 agonists. Here, we show that the chloride channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) is also a GPR35 agonist. NPPB activates the GPR35-Gi/o and GPR35-G16 pathways in human embryonic kidney 293 (HEK293) cells and induces intracellular calcium mobilization in a concentration-dependent manner in HEK293 cells coexpressing human, rat or mouse GPR35 and the chimeric G protein G(qi5). These results suggest a novel pharmacological activity of NPPB and will provide useful information to search for more potent and selective GPR35 agonists.
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PMID:5-Nitro-2-(3-phenylpropylamino)benzoic acid is a GPR35 agonist. 1881 9

Heart failure (HF) is a common disease that continues to be associated with high morbidity and mortality warranting novel therapeutic strategies. Cyclic guanosine monophosphate (cGMP) is the second messenger of several important signaling pathways based on distinct guanylate cyclases (GCs) in the cardiovascular system. Both the nitric oxide/soluble GC (NO/sGC) as well as the natriuretic peptide/GC-A (NP/GC-A) systems are disordered in HF, providing a rationale for their therapeutic augmentation. Soluble GC activation with conventional nitrovasodilators has been used for more than a century but is associated with cGMP-independent actions and the development of tolerance, actions which novel NO-independent sGC activators now in clinical development lack. Activation of GC-A by administration of naturally occurring or designer natriuretic peptides is an emerging field, as is the inhibition of enzymes that degrade endogenous NPs. Finally, inhibition of cGMP-degrading phosphodiesterases, particularly phosphodiesterase 5 provides an additional strategy to augment cGMP-signaling.
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PMID:Modulation of cGMP in heart failure: a new therapeutic paradigm. 1908 42

Cyclic GMP, guanosine 3',5'-cyclic monophosphate, is a critical and multifunctional second-messenger molecule that mediates diverse physiological and pathophysiological functions in cardiac and vascular tissues. Synthesized through nitric oxide, carbon monoxide, and/or natriuretic peptide-mediated guanylate cyclase stimulation and guanosine triphosphate dephosphorylation, cyclic GMP is capable of stimulating a cascade of serine/threonine kinase events, including signaling through cyclic GMP- and/or cyclic AMP-dependent protein kinases, eliciting protein kinase-independent actions such as modulation of ion channels or transporters, or undergoing hydrolytic degradation through actions of cyclic GMP-regulated phosphodiesterases. Substrates, enzymes, cofactors, and associated variables in this multifaceted system have historically been targets of vital pharmacotherapies with perhaps most common the use of vascular smooth muscle-targeting organonitrates in cardiac patients and phosphodiesterase inhibitors in individuals with erectile dysfunction. Accumulating basic science and clinical evidence, however, suggests that cyclic GMP signaling is compromised under conditions of disease or elevated physiological stresses. Moreover, nitric oxide can stimulate an array of cytotoxic effects and nitric oxide-based therapies can be limited by diminished bioactivity and the development of tachyphylaxis or tolerance after prolonged use. Consequently, an emerging area for clinical drug development and therapeutic drug evaluation for conditions of cardiovascular adversity has focused on identification of cyclic GMP signaling pathways that act under oxidized or nitric oxide-unresponsive conditions and/or that operate irrespective of nitric oxide-induced complications. The aim of this therapeutic review is to describe novel, nitric oxide-alternate avenues for cyclic GMP signaling in vascular smooth muscle growth with particular emphasis on pharmacotherapeutics of recently characterized cyclic GMP-specific approaches.
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PMID:Novel therapies for cyclic GMP control of vascular smooth muscle growth. 1912 40

ACTH-stimulated aldosterone secretion can be inhibited by atrio-natriuretic peptide/cGMP. The mechanism behind this modulation has been reported to involve cGMP-dependent activation of phosphodiesterase 2 (PDE2) and hydrolysis of cAMP. Recently it was reported that activation of cGMP-dependent protein kinase II (cGKII) stimulated aldosterone secretion in rat zona glomerulosa cells. The zona glomerulosa of the murine adrenal cortex expresses cGKII and PDE2. We used mice with a homozygous inactivation of the cGKII gene to investigate in vivo the potential role of this kinase in aldosterone secretion. Basal plasma renin and aldosterone levels were similar in wild-type and cGKII(-/-) mice. In vivo injection of atrio-natriuretic peptide decreased ACTH-stimulated aldosterone secretion in wild-type mice, but had no effect in cGKII-deficient mice. These results support the view that cGKII modulates aldosterone secretion in the murine adrenal cortex.
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PMID:cGMP-dependent protein kinase II and aldosterone secretion. 1915 45

Red blood cell distribution width (RDW), a widely available biomarker, independently predicts adverse outcomes in left-sided heart failure. The relation between RDW and death in pulmonary hypertension (PH) is unknown. In a prospective study of 162 consecutive patients with PH, RDW was recorded during initial diagnostic right-sided cardiac catheterization, and patients were followed for 2.1 +/- 0.8 years to determine vital status. Demographic, clinical, laboratory, and hemodynamic variables were compared by tertile of RDW. Cox proportional-hazards models were used to determine whether RDW was independently associated with death, and the prognostic utility of RDW was compared to that of other laboratory predictors, including N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP). Of the 162 study patients, 78% were women, and 62% had pulmonary arterial hypertension. The mean age was 53 +/- 15 years, and most patients had severe PH (mean pulmonary artery pressure 48 +/- 13 mm Hg). The highest tertile of RDW predicted death (univariate hazard ratio 4.86, 95% confidence interval 1.37 to 17.29, p = 0.015; multivariate hazard ratio 2.4, 95% confidence interval 1.02 to 5.84, p = 0.045, after adjusting for age, gender, diabetes mellitus, connective tissue disease, diuretic use, phosphodiesterase inhibitor use, hemoglobin, mean corpuscular volume, and blood urea nitrogen [BUN]). Of the laboratory data, only RDW, BUN, and NT-pro-BNP were associated with death on univariate analysis. When RDW, BUN, and NT-pro-BNP were entered into a multivariate model, only RDW was still associated with death (p = 0.037 for RDW, p = 0.18 for BUN, and p = 0.39 for NT-pro-BNP). Adding NT-pro-BNP to RDW did not improve the prediction of mortality. In conclusion, RDW is independently associated with death in patients with PH and performs better as a prognostic indicator than NT-pro-BNP.
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PMID:Usefulness of red cell distribution width as a prognostic marker in pulmonary hypertension. 1973 26

In vascular smooth muscle cells, relaxant actions of guanosine--3',5'-cyclic monophosphate (cGMP) are well recognized, but there is increasing evidence that cGMP also plays regulatory roles in vascular endothelium. However, the autacoid and endocrine mechanisms controlling cGMP production in endothelium are not well understood. The objective of these studies was to examine the mechanisms of cGMP accumulation in human umbilical vein endothelial cells (HUVEC) in response to natriuretic peptides. Expression in HUVEC of natriuretic peptide receptors, particulate guanylyl cyclases (GC)-A and GC-B, was confirmed by RT-PCR and Western blot analysis. In the presence of the phosphodiesterase inhibitor IBMX 500 microM, 3 h incubation of HUVEC with B-type natriuretic peptide (BNP) (preferential GC-A agonist) or C-type natriuretic peptide (CNP) (preferential GC-B agonist) stimulated concentration-dependent increases in cGMP production. At 10 and 100 nM, we observed two to three-fold greater potency of CNP compared to BNP. In the absence of IBMX, CNP-stimulated cGMP accumulation was significantly less than cGMP accumulation in response to sodium nitroprusside 1 mM. This greater sensitivity of GC-B-derived cGMP to phosphodiesterases suggests compartmentalization of two pools of cGMP from particulate and soluble guanylyl cyclases. Although CNP 100 nM and 1 microM was observed to increase nitrite + nitrate (stable metabolites of NO) production in HUVEC two-fold above basal level, the soluble guanylyl cyclase inhibitor ODQ 10 microM did not significantly modify CNP-stimulated cGMP accumulation suggesting that endothelial actions of CNP may be NO-independent. In conclusion, these studies indicate functional signaling by natriuretic peptides in endothelial cells, supporting possible roles of these mediators in regulating endothelial cell function.
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PMID:C-type natriuretic peptide regulation of guanosine-3',5'-cyclic monophosphate production in human endothelial cells. 2008 72

The aim of this study was to evaluate the relative contributions of various hormones involved in the regulation of lipid mobilization in subcutaneous adipose tissue (SCAT) during exercise and to assess the impact of obesity on this regulation. Eight lean and eight obese men performed a 60-min cycle exercise bout at 50% of their peak oxygen uptake on two occasions: during intravenous infusion of octreotide (a somatostatin analog) or physiological saline (control condition). Lipolysis in SCAT was evaluated using in situ microdialysis. One microdialysis probe was perfused with the adrenergic blockers phentolamine and propranolol while another probe was perfused with the phosphodiesterase and adenosine receptor inhibitor aminophylline. Compared with the control condition, infusion of octreotide reduced plasma insulin levels in lean (from approximately 3.5 to 0.5 microU/ml) and in obese (from approximately 9 to 2 microU/ml), blunted the exercise-induced rise in plasma GH and epinephrine levels in both groups, and enhanced the exercise-induced natriuretic peptide (NP) levels in lean but not in obese subjects. In both groups, octreotide infusion resulted in higher exercise-induced increases in dialysate glycerol concentrations in the phentolamine-containing probe while no difference in lipolytic response was found in the aminophylline-containing probe. The results suggest that insulin antilipolytic action plays a role in the regulation of lipolysis during exercise in lean as well as in obese subjects. The octreotide-induced enhancement of exercise lipolysis in lean subjects was associated with an increased exercise-induced plasma NP response. Adenosine may contribute to the inhibition of basal lipolysis in both subject groups.
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PMID:Lipid mobilization in subcutaneous adipose tissue during exercise in lean and obese humans. Roles of insulin and natriuretic peptides. 2048 12


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