Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies implicate increased cGMP synthesis as a postreceptor contributor to reduced cardiac sympathetic responsiveness. Here we provide the first evidence that modulation of this interaction by cGMP-specific phosphodiesterase PDE5A is also diminished in failing hearts, providing a novel mechanism for blunted beta-adrenergic signaling in this disorder. In normal conscious dogs chronically instrumented for left ventricular pressure-dimension analysis, PDE5A inhibition by EMD82639 had modest basal effects but markedly blunted dobutamine-enhanced systolic and diastolic function. In failing hearts (tachypacing model), however, EMD82639 had negligible effects on either basal or dobutamine-stimulated function. Whole myocardium from failing hearts had 50% lower PDE5A protein expression and 30% less total and EMD92639-inhibitable cGMP-PDE activity. Although corresponding myocyte protein and enzyme activity was similar among groups, the proportion of EMD82639-inhibitable activity was significantly lower in failure cells. Immunohistochemistry confirmed PDE5A expression in both the vasculature and myocytes of normal and failing hearts, but there was loss of z-band localization in failing myocytes that suggested altered intracellular localization. Thus, PDE5A regulation of cGMP in the heart can potently modulate beta-adrenergic stimulation, and alterations in enzyme localization and reduced synthesis may blunt this pathway in cardiac failure, contributing to dampening of the beta-adrenergic response.
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PMID:Cardiac phosphodiesterase 5 (cGMP-specific) modulates beta-adrenergic signaling in vivo and is down-regulated in heart failure. 1148 Dec 19

Left ventricular hypertrophy leads to heart failure and represents a high risk leading to premature death. Cyclic nucleotides (cAMP and cGMP) play a major role in heart contractility and cyclic nucleotide phosphodiesterases (PDEs) are involved in different stages of advanced cardiac diseases. We have investigated their contributions in the very initial stages of left ventricular hypertrophy development. Wistar male rats were treated over two weeks by chronic infusion of angiotensin II using osmotic mini-pumps. Left cardiac ventricles were used as total homogenates for analysis. PDE1 to PDE5 specific activities and protein and mRNA expressions were explored.Rats developed arterial hypertension associated with a slight cardiac hypertrophy (+24%). cAMP-PDE4 activity was specifically increased while cGMP-PDE activities were broadly increased (+130% for PDE1; +76% for PDE2; +113% for PDE5) and associated with increased expressions for PDE1A, PDE1C and PDE5A. The cGMP-PDE1 activation by Ca(2+)/CaM was reduced. BNP expression was increased by 3.5-fold, while NOX2 expression was reduced by 66% and AMP kinase activation was increased by 64%. In early cardiac hypertrophy induced by angiotensin II, all specific PDE activities in left cardiac ventricles were increased, favoring an increase in cGMP hydrolysis by PDE1, PDE2 and PDE5. Increased cAMP hydrolysis was related to PDE4. We observed the establishment of two cardioprotective mechanisms and we suggest that these mechanisms could lead to increase intracellular cGMP: i) increased expression of BNP could increase "particulate" cGMP pool; ii) increased activation of AMPK, subsequent to increase in PDE4 activity and 5'AMP generation, could elevate "soluble" cGMP pool by enhancing NO bioavailability through NOX2 down-regulation. More studies are needed to support these assumptions. Nevertheless, our results suggest a potential link between PDE4 and AMPK/NOX2 and they point out that cGMP-PDEs, especially PDE1 and PDE2, may be interesting therapeutic targets in preventing cardiac hypertrophy.
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PMID:Concerted regulation of cGMP and cAMP phosphodiesterases in early cardiac hypertrophy induced by angiotensin II. 2115 82

cGMP and its primary target kinase, protein kinase G (PKG), are well recognized modulators of cardiac function and the chronic stress response. Their enhancement appears to serve as a myocardial brake, reducing maladaptive hypertrophy, improving cell survival, signaling and mitochondrial function, protecting against ischemia/reperfusion injury, and blunting the stimulatory effects of catecholamines. Translation of these effects into a chronic treatment for patients with heart failure based on increasing the generation of cGMP has been difficult, however, with tolerance and hypotension effects occurring with nitrates and neutral responses to natriuretic peptides (at least B-type). Inhibition of cGMP-targeted phosphodiesterases (PDEs) such as PDE5A is an alternative approach that appears to have more potent effects. Recent studies in experimental models and patients are revealing benefits in heart failure syndromes, and ongoing multicenter trials are testing the efficacy of PDE5A inhibition. In this review we discuss recent research findings and controversies regarding the PDE/cGMP/PKG signaling pathway, and suggest directions for further research.
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PMID:Phosphodiesterases and cardiac cGMP: evolving roles and controversies. 2147 71

Phosphodiesterase (PDE) enzymes are widely distributed throughout the body, having numerous effects and functions. The use of on demand PDE5 inhibitors (-Is) for the treatment of erectile dysfunction (ED) has recently obtained approval for chronic daily dosing for the same indication. There are published data supporting the use of PDE5-Is for the treatment of lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH). Additional reports suggest benefit by these agents in patients with chronic heart failure, pulmonary hypertension, essential hypertension, and for the treatment of ischemia. Various central nervous system disorders have been described as targets by PDE5-Is. Sildenafil may have a potential therapeutic indication as a cognitive enhancer in age-related cerebral conditions. There is preclinical evidence for further investigation of the use of PDE5A -Is to improve recovery of cerebral function in humans after stroke by enhancing angiogenesis, neurogenesis and improving neurologic function. Sildenafil delays intestinal ulceration by an increase in the secretion of mucus/fluid and a decrease in hypermotility, and has a protective effect in reducing gastric damage. Larger scale, well designed clinical trials are needed to ascertain the safety, efficacy and cost-effectiveness of PDE5-Is in the future treatment of both urologic and non-urologic diseases. In this review, potential applications of PDE5-Is on urologic, cardiovascular, gastrointestinal, and central nervous system disorders will be updated.
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PMID:PDE5 inhibitor treatment options for urologic and non-urologic indications: 2012 update. 2274 25

The number of patients with heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) is increasing, and for HFpEF, no therapies have clinical benefit. It has been hypothesized that PKG attenuates pathological remodelling, and increasing cGMP would be beneficial for patients with HF. However, neither the RELAX nor NEAT-HFpEF trial showed benefit. But there is still enthusiasm for increasing cGMP in patients with HF, which highlight the need to determine the expression of PDEs in cardiac muscle. This study used immunoblotting to examine the expression of the PDEs that have been suggested to be targets for therapy of HF in both canines (normal and HFpEF) and humans (normal and HFrEF). Our results demonstrate PDE1C and PDE3A are expressed in cardiac muscle, but we could not detect the expression of PDE2A, PDE5A, PDE7A and PDE9A in cardiac tissue lysates from either normal or failing hearts. Thus, one should not expect a clinical benefit for a therapy targeting these PDEs in heart failure, which highlights the importance of rigorous demonstration of the target of therapy prior to undertaking a clinical trial.
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PMID:Phosphodiesterase expression in the normal and failing heart. 3055 Jul 27

Cyclic nucleotide phosphodiesterases comprise an 11-member superfamily yielding near 100 isoform variants that hydrolyze cAMP or cGMP to their respective 5'-monophosphate form. Each plays a role in compartmentalized cyclic nucleotide signaling, with varying selectivity for each substrate, and conveying cell and intracellular-specific localized control. This review focuses on the 5 phosphodiesterases (PDEs) expressed in the cardiac myocyte capable of hydrolyzing cGMP and that have been shown to play a role in cardiac physiological and pathological processes. PDE1, PDE2, and PDE3 catabolize cAMP as well, whereas PDE5 and PDE9 are cGMP selective. PDE3 and PDE5 are already in clinical use, the former for heart failure, and PDE1, PDE9, and PDE5 are all being actively studied for this indication in patients. Research in just the past few years has revealed many novel cardiac influences of each isoform, expanding the therapeutic potential from their selective pharmacological blockade or in some instances, activation. PDE1C inhibition was found to confer cell survival protection and enhance cardiac contractility, whereas PDE2 inhibition or activation induces beneficial effects in hypertrophied or failing hearts, respectively. PDE3 inhibition is already clinically used to treat acute decompensated heart failure, although toxicity has precluded its long-term use. However, newer approaches including isoform-specific allosteric modulation may change this. Finally, inhibition of PDE5A and PDE9A counter pathological remodeling of the heart and are both being pursued in clinical trials. Here, we discuss recent research advances in each of these PDEs, their impact on the myocardium, and cardiac therapeutic potential.
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PMID:Myocardial Phosphodiesterases and Their Role in cGMP Regulation. 3165 71