Compartmentalization of Cardiac β-Adrenergic Inotropy Modulation by Phosphodiesterase Type 5

Takimoto, Eiki; Belardi, Diego; Tocchetti, Carlo G.; Vahebi, Susan; Cormaci, Gianfrancesco; Ketner, Elizabeth; Moens, An L.; Champion, Hunter C.; Kass, David A.

doi:10.1161/circulationaha.106.643536

Cited by 149 publications

(139 citation statements)

References 46 publications

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“…Recently, compartmentalized [cGMP] i was reported in cardiac myocytes through specific activation of pGC by natriuretic peptides (15,19,21). These studies also suggested that cGMP-specific PDEs maintain these local patterns of [cGMP] i elicited through pGC.…”

Section: Spatial and Temporal Dynamics Of No-and Anp-induced Cgmp Sig-mentioning

confidence: 90%

“…FRETbased cGMP indicators are also limited in resolving possible compartmentalized intracellular cGMP signaling events using confocal microscopy. It was recently suggested that in VSM cells and cardiac myocytes cGMP signaling may be spatially segregated and that this functional compartmentalization may be the cause of the unique actions of ANP and NO (19)(20)(21)(22)(23). The goal of this study was to develop previously undescribed non-FRET biosensors suitable to monitor the temporal changes of [cGMP] i in response to low-nanomolar NO or ANP, and to investigate the spatial patterning of [cGMP] i , using real-time, confocal imaging techniques.…”

mentioning

confidence: 99%

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Differential patterning of cGMP in vascular smooth muscle cells revealed by single GFP-linked biosensors

Nausch

Ledoux

Bonev

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

153

174

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Section: Spatial and Temporal Dynamics Of No-and Anp-induced Cgmp Sig-mentioning

confidence: 90%

mentioning

confidence: 99%

Differential patterning of cGMP in vascular smooth muscle cells revealed by single GFP-linked biosensors

Nausch

Ledoux

Bonev

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

153

174

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“…89 Son zamanlarda köpek, sıçan ve fareler üzerinde yapılan çalışmalarda, PDE5'in beta (β) reseptörleri aracılığı ile kardiyak yanıtları düzenlediği gösterilmiştir. 90 85-kDa PDE5 esas insan plateletlerinde ifade edilmiş ve plateletlerin ana cGMP-PDE hidrolitik aktivitesiyle temsil edildiği ortaya çıkarılmıştır. 91 …”

Section: Dağılımunclassified

Phosphodiesterase Enzymes and Inhibitors: Review

Tuğrak¹,

Küçükoğlu²

2016

Turkiye Klinikleri J Pharm Sci

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Ö ÖZ ZE ET T Siklik nükleotid fosfodiesteraz enzimleri, vücutta her dokuda ve hücrede bulunabilen enzimlerdir. cAMP ve cGMP'yi hidroliz ettikleri için hücre sinyallerinde önemli rol oynarlar. PDE süper ailesi PDE1-PDE11 arasında olmak üzere 11 tanedir. Memeli hücrelerinde her bir aile 20'den fazla gen vermek için birdört farklı gen taşımaktadır. Bu genler 50'den fazla farklı PDE proteinini kodlarlar. PDE enzimleri içerisinde özellikle PDE1 ve PDE6 iyi karakterize edilmiş izozimlerdir. PDE'ler hücre ve dokularda spesifik dağılım gösteren enzimlerdir. Vücudun farklı doku ve organlarında bulunan PDE enzimleri farklılık gösterir. Bu sayede çeşitli hücre fonksiyonlarında farklı fizyolojik olaylara aracılık edebilirler. PDE izoenzimlerinin hücre ve doku fonksiyonlarına özel katkıları ve patofizyolojik düzenlenmeleri bugün önemli bir araştırma alanı oluşturmaktadır. Bu durum, etkileri henüz tam olarak belirlenmediği için özellikle PDE7-PDE11 gibi yeni PDE ailelerini daha çok ilgilendirmektedir. İnflamasyon, nörodejenerasyon ve kanser gibi birçok patolojik durumda meydana gelen değişiklikler, hücre içi sinyallerle ilgili PDE'lerin serbestleşmesini, bu patolojilerin önlenmesini, ayrıca bu tür patolojik durumların tedavisinde gözlemle-nen zorlukları açıklayabilir. Bu konularda yapılacak araştırmalar sonucu elde edilecek bulgular henüz kesin tedavisi bulunmayan hastalıkların tedavisinde yeni gelişmelere yol açabilir. Bu çalışmada, PDE enzimlerinin özellikleri, vücutta bulundukları doku ve organlar ile patofizyolojik olaylardaki rolleri açık-lanmış, ilaveten PDE inhibitörü ilaçlar anlatılmıştır. Ayrıca yeni geliştirilen ve ruhsatlandırma çalışmaları devam eden PDE inhibitörü bileşikler hakkında da bilgi verilmiştir.A An na ah ht ta ar r K Ke el li im me el le er r: : Fosfodiesteraz inhibitörleri; 2',3'-siklik AMP; 2',3'-siklik GMP A AB BS ST TR RA AC CT T Cyclic nucleotide phosphodiesterase enzymes can be found in every tissue and cell in the body. They play an important role in cell signaling because they hydrolyze cAMP and cGMP. PDE superfamily is 11 units, including PDE1-PDE11. Each family in mammalian cells encompasses 1 to 4 distinct genes, to give more than 20 genes. These genes encode more than 50 different PDE proteins. PDE enzymes in particular PDE1 and PDE6 are isozymes have been well characterized. PDEs are enzymes exhibiting specific distribution in cells and tissues. PDE enzymes located in different tissues and organs of the body vary. In this way, they can mediate different physiological events in various cell functions. Today, private contributions and pathophysiological regulations of PDE isoenzymes in cell and tissue functions constitute an important research field. This situation is more relevant for especially new PDE families such as PDE7-PDE11, because their effects have not been fully determined. Changes that occurs in many pathological situations such as inflammation, neurodegeneration and cancer, may explain the liberalization of PDEs related to the intracellular signaling as well as prevention of th...

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“…A recent study indicated that PDE5 was not present in normal human left and right ventricular myocardium [169] . However, there has been strong evidence showing PDE5 expression in the left ventricle and isolated cardiomyocytes from dog [170] and mouse [171,172] as well as hypertrophied human left and right ventricles [169] . PDE5 enzymes are specific in the hydrolysis of cGMP and also contain high affinity binding sites for cGMP [173] .…”

Section: Phosphodiesterasementioning

confidence: 99%

“…PDE5 enzymes are specific in the hydrolysis of cGMP and also contain high affinity binding sites for cGMP [173] . Interestingly, PDE5 appears to regulate a distinct pool of cGMP that is separate from that produced by atrial natriuretic peptide stimulation of pGC suggesting that it plays a role in compartmentalization of cGMP signaling [172] .…”

Section: Phosphodiesterasementioning

confidence: 99%

Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts

Rao

2008

Acta Pharmacol Sin

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Phosphodiesterases (PDEs) are enzymes that degrade cellular cAMP and cGMP and are thus essential for regulating the cyclic nucleotides. At least 11 families of PDEs have been identified, each with a distinctive structure, activity, expression, and tissue distribution. The PDE type-3, -4, and -5 (PDE3, PDE4, PDE5) are localized to specific regions of the cardiomyocyte, such as the sarcoplasmic reticulum and Z-disc, where they are likely to influence cAMP/cGMP signaling to the end effectors of contractility. Several PDE inhibitors exhibit remarkable hemodynamic and inotropic properties that may be valuable to clinical practice. In particular, PDE3 inhibitors have potent cardiotonic effects that can be used for short-term inotropic support, especially in situations where adrenergic stimulation is insufficient. Most relevant to this review, PDE inhibitors have also been found to have cytoprotective effects in the heart. For example, PDE3 inhibitors have been shown to be cardioprotective when given before ischemic attack, whereas PDE5 inhibitors, which include three widely used erectile dysfunction drugs (sildenafil, vardenafil and tadalafil), can induce remarkable cardioprotection when administered either prior to ischemia or upon reperfusion. This article provides an overview of the current laboratory and clinical evidence, as well as the cellular mechanisms by which the inhibitors of PDE3, PDE4 and PDE5 exert their beneficial effects on normal and ischemic hearts. It seems that PDE inhibitors hold great promise as clinically applicable agents that can improve cardiac performance and cell survival under critical situations, such as ischemic heart attack, cardiopulmonary bypass surgery, and heart failure.

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Compartmentalization of Cardiac β-Adrenergic Inotropy Modulation by Phosphodiesterase Type 5

Cited by 149 publications

References 46 publications

Differential patterning of cGMP in vascular smooth muscle cells revealed by single GFP-linked biosensors

Differential patterning of cGMP in vascular smooth muscle cells revealed by single GFP-linked biosensors

Phosphodiesterase Enzymes and Inhibitors: Review

Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts

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