Small-molecule allosteric activators of PDE4 long form cyclic AMP phosphodiesterases

Omar, Faisa; Findlay, J. N.; Carfray, Gemma; Allcock, Robert W.; Jiang, Zhong Tao; Moore, Caitlin; Muir, Amy L.; Lannoy, Morgane; Fertig, Bracy A.; Mai, Deborah; Day, Jonathan P.; Bolger, Graeme B.; Baillie, George S.; Schwiebert, Erik M.; Klußmann, Jens Peter; Pyne, Nigel J.; Ong, Albert; Bowers, Keith; Adam, Jennifer; Adams, David H.; Houslay, Miles D.; Henderson, David

doi:10.1073/pnas.1822113116

Cited by 60 publications

(55 citation statements)

References 72 publications

(165 reference statements)

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“…17 Recently, a small allosteric modulator that mimics the effect of PKA phosphorylation on PDE4 long forms was reported. 50 This prototypical PDE4 activator was shown to reduce the chronically elevated cAMP levels which drive abnormal cyst formation in animal and human cell models of autosomal dominant polycystic kidney disease. 50 These results suggest that such compound could constitute an alternative approach to gene therapy in HF.…”

Section: Discussionmentioning

confidence: 99%

Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure

Karam

Margaria²,

Bourcier

et al. 2020

Circulation

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Background: The cyclic AMP (adenosine monophosphate; cAMP)-hydrolyzing protein PDE4B (phosphodiesterase 4B) is a key negative regulator of cardiac β-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal Ca 2+ handling and PDE4B is decreased in pressure overload hypertrophy, suggesting that increasing PDE4B in the heart is beneficial in heart failure. Methods: We measured PDE4B expression in human cardiac tissues and developed 2 transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B and an adeno-associated virus serotype 9 encoding PDE4B. Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Also, cAMP and PKA (cAMP dependent protein kinase) activity were monitored by Förster resonance energy transfer, L-type Ca 2+ current by whole-cell patch-clamp, and cardiomyocyte shortening and Ca 2+ transients with an Ionoptix system. Heart failure was induced by 2 weeks infusion of isoproterenol or transverse aortic constriction. Cardiac remodeling was evaluated by serial echocardiography, morphometric analysis, and histology. Results: PDE4B protein was decreased in human failing hearts. The first PDE4B-transgenic mouse line (TG15) had a ≈15-fold increase in cardiac cAMP-PDE activity and a ≈30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basal ex vivo myocardial function was unchanged, but β-adrenergic receptor stimulation of cardiac inotropy, cAMP, PKA, L-type Ca 2+ current, Ca 2+ transients, and cell contraction were blunted. Endurance capacity and life expectancy were normal. Moreover, these mice were protected from systolic dysfunction, hypertrophy, lung congestion, and fibrosis induced by chronic isoproterenol treatment. In the second PDE4B-transgenic mouse line (TG50), markedly higher PDE4B overexpression, resulting in a ≈50-fold increase in cardiac cAMP-PDE activity caused a ≈50% decrease in fractional shortening, hypertrophy, dilatation, and premature death. In contrast, mice injected with adeno-associated virus serotype 9 encoding PDE4B (10 12 viral particles/mouse) had a ≈50% increase in cardiac cAMP-PDE activity, which did not modify basal cardiac function but efficiently prevented systolic dysfunction, apoptosis, and fibrosis, while attenuating hypertrophy induced by chronic isoproterenol infusion. Similarly, adeno-associated virus serotype 9 encoding PDE4B slowed contractile deterioration, attenuated hypertrophy and lung congestion, and prevented apoptosis and fibrotic remodeling in transverse aortic constriction. Conclusions: Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat heart failure.

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Section: Discussionmentioning

confidence: 99%

Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure

Karam

Margaria²,

Bourcier

et al. 2020

Circulation

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“…In contrast, PDE activators may be developed to treat cancers that are promoted by cAMP signaling. Recently, a small-molecule compound that allosterically activates PDE4 long isoforms has been developed [ 142 ]. This prototypical PDE4 activator compound is able to reduce intracellular cAMP levels and inhibit cyst formation in the kidney [ 142 ].…”

Section: Targeting Camp–pka Pathway For Cancer Therapymentioning

confidence: 99%

“…Recently, a small-molecule compound that allosterically activates PDE4 long isoforms has been developed [ 142 ]. This prototypical PDE4 activator compound is able to reduce intracellular cAMP levels and inhibit cyst formation in the kidney [ 142 ]. It remains to know whether such kinds of PDE activators may be repurposed to treat some types of cancer.…”

Section: Targeting Camp–pka Pathway For Cancer Therapymentioning

confidence: 99%

Complex roles of cAMP–PKA–CREB signaling in cancer

et al. 2020

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Cyclic adenosine monophosphate (cAMP) is the first discovered second messenger, which plays pivotal roles in cell signaling, and regulates many physiological and pathological processes. cAMP can regulate the transcription of various target genes, mainly through protein kinase A (PKA) and its downstream effectors such as cAMP-responsive element binding protein (CREB). In addition, PKA can phosphorylate many kinases such as Raf, GSK3 and FAK. Aberrant cAMP–PKA signaling is involved in various types of human tumors. Especially, cAMP signaling may have both tumor-suppressive and tumor-promoting roles depending on the tumor types and context. cAMP–PKA signaling can regulate cancer cell growth, migration, invasion and metabolism. This review highlights the important roles of cAMP–PKA–CREB signaling in tumorigenesis. The potential strategies to target this pathway for cancer therapy are also discussed.

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“…One allosteric activator compound of PDE4 has the potential to lower the cAMP levels and limit the cAMP-mediated signaling pathways. This inhibits the cyst formation after tests in human embryonic kidney (HEK) 293 and Madin Darby Canine Kidney (MDCK, ATCC) cells [ 58 ]. Manipulating the N -terminal regulatory modules or upstream interventions could give new insights into the regulating mechanism of PDE catalytic activity.…”

Section: Therapeutic Targeting Of Pdesmentioning

confidence: 99%

Advances, Perspectives and Potential Engineering Strategies of Light-Gated Phosphodiesterases for Optogenetic Applications

Tian

Yang

Gao

2020

IJMS

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The second messengers, cyclic adenosine 3′-5′-monophosphate (cAMP) and cyclic guanosine 3′-5′-monophosphate (cGMP), play important roles in many animal cells by regulating intracellular signaling pathways and modulating cell physiology. Environmental cues like temperature, light, and chemical compounds can stimulate cell surface receptors and trigger the generation of second messengers and the following regulations. The spread of cAMP and cGMP is further shaped by cyclic nucleotide phosphodiesterases (PDEs) for orchestration of intracellular microdomain signaling. However, localized intracellular cAMP and cGMP signaling requires further investigation. Optogenetic manipulation of cAMP and cGMP offers new opportunities for spatio-temporally precise study of their signaling mechanism. Light-gated nucleotide cyclases are well developed and applied for cAMP/cGMP manipulation. Recently discovered rhodopsin phosphodiesterase genes from protists established a new and direct biological connection between light and PDEs. Light-regulated PDEs are under development, and of demand to complete the toolkit for cAMP/cGMP manipulation. In this review, we summarize the state of the art, pros and cons of artificial and natural light-regulated PDEs, and discuss potential new strategies of developing light-gated PDEs for optogenetic manipulation.

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Small-molecule allosteric activators of PDE4 long form cyclic AMP phosphodiesterases

Cited by 60 publications

References 72 publications

Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure

Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure

Complex roles of cAMP–PKA–CREB signaling in cancer

Advances, Perspectives and Potential Engineering Strategies of Light-Gated Phosphodiesterases for Optogenetic Applications

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