Phosphodiesterase type 3A (PDE3A), but not type 3B (PDE3B), contributes to the adverse cardiac remodeling induced by pressure overload

Polidovitch, Nazari; Yang, Sibao; Sun, Huan; Lakin, Robert; Ahmad, Faiyaz; Gao, Xiao‐Dong; Turnbull, Patrick C.; Chiarello, Carmelina; Perry, Christopher G. R.; Manganiello, Vincent; Yang, Ping; Backx, Peter H.

doi:10.1016/j.yjmcc.2019.04.028

Cited by 17 publications

(9 citation statements)

References 55 publications

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“…Cardiac pressure overload is a well-known contributor to electrical and structural remodeling of the heart and a risk factor for cardiac arrhythmias [39,40]. In line with the literature we observed that TAC surgery induced hypertrophy, impaired cardiac contractility, and increased susceptibility for arrhythmias; however, PKP2-Hz mice presented similar effects as WT mice [21,39].…”

Section: Discussionsupporting

confidence: 77%

“…TAC surgery increased collagen abundance predominantly in PKP2-Hz hearts. This implicates that PKP2 is involved in regulating the cardiac fibrotic response, as PKP2 haploinsufficiency might lead to activation of pro-fibrotic pathways, inflammation, and apoptosis [40,41]. Enhanced ß-catenin levels in PKP2-Hz TAC mice might confirm this hypothesis, since a loss of desmosomal integrity alters the Wnt-signalling pathway, a well-known contributor to adipo-and fibrogenensis and ACM pathology [42].…”

Section: Discussionmentioning

confidence: 99%

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Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress

Opbergen

Noorman

Pfenniger

et al. 2019

IJMS

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Human variants in plakophilin-2 (PKP2) associate with most cases of familial arrhythmogenic cardiomyopathy (ACM). Recent studies show that PKP2 not only maintains intercellular coupling, but also regulates transcription of genes involved in Ca2+ cycling and cardiac rhythm. ACM penetrance is low and it remains uncertain, which genetic and environmental modifiers are crucial for developing the cardiomyopathy. In this study, heterozygous PKP2 knock-out mice (PKP2-Hz) were used to investigate the influence of exercise, pressure overload, and inflammation on a PKP2-related disease progression. In PKP2-Hz mice, protein levels of Ca2+-handling proteins were reduced compared to wildtype (WT). PKP2-Hz hearts exposed to voluntary exercise training showed right ventricular lateral connexin43 expression, right ventricular conduction slowing, and a higher susceptibility towards arrhythmias. Pressure overload increased levels of fibrosis in PKP2-Hz hearts, without affecting the susceptibility towards arrhythmias. Experimental autoimmune myocarditis caused more severe subepicardial fibrosis, cell death, and inflammatory infiltrates in PKP2-Hz hearts than in WT. To conclude, PKP2 haploinsufficiency in the murine heart modulates the cardiac response to environmental modifiers via different mechanisms. Exercise upon PKP2 deficiency induces a pro-arrhythmic cardiac remodeling, likely based on impaired Ca2+ cycling and electrical conduction, versus structural remodeling. Pathophysiological stimuli mainly exaggerate the fibrotic and inflammatory response.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress

Opbergen

Noorman

Pfenniger

et al. 2019

IJMS

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“…In some studies of human failing hearts, no change in PDE3 activity was reported 162,177 , whereas decreased PDE3 activity was found in others 178 . Similarly, in animal models of cardiac hypertrophy or HF, decreased PDE3 activity or PDE3A expression was reported in some studies [178][179][180][181][182][183] and increased activity or expression in others [184][185][186][187] .…”

Section: [H1] Pdes In Cardiac Hypertrophy and Hfmentioning

confidence: 72%

“…Herein, the cardioprotective effects of PDE3B were dependent on cAMP-PKA signalling, which potentiated the opening of Ca 2+ -activated potassium channels, decreasing reactive oxygen species formation by mitochondrial fractions that were resistant to calcium-induced mitochondrial permeability transition pore opening 167 . In a TAC mouse model, milrinone was shown to attenuate ventricular remodelling, decrease fibrosis and macrophage infiltration and de-activate the p38 MAPK pathway 185 . Global knock out of Pde3a provided protection against ventricular remodelling similar to that induced by TAC, and milrinone had no additional effect in these mice 185 .…”

Section: [H1] Pdes In Cardiac Hypertrophy and Hfmentioning

confidence: 99%

Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiac hypertrophy and heart failure

et al. 2022

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HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

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“…Both the expression and activity of PDE3A are diminished in pre-clinical models of pressure overload and in failing human hearts [121,126]. Pharmacological inhibition of PDE3 has been reported to blunt TAC-stimulated hypertrophy and fibrosis, an effect recapitulated in PDE3A −/− , but not PDE3B −/− , mice [127]. Conversely, genetic ablation of PDE3B, but not PDE3A, counteracts the adverse effects of IRI [128].…”

Section: Heart Failure Pathophysiologymentioning

confidence: 99%

Cardiac Cyclic Nucleotide Phosphodiesterases: Roles and Therapeutic Potential in Heart Failure

Preedy

2020

Cardiovasc Drugs Ther

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The cyclic nucleotides cyclic adenosine-3′,5′-monophosphate (cAMP) and cyclic guanosine-3′,5′-monophosphate (cGMP) maintain physiological cardiac contractility and integrity. Cyclic nucleotide-hydrolysing phosphodiesterases (PDEs) are the prime regulators of cAMP and cGMP signalling in the heart. During heart failure (HF), the expression and activity of multiple PDEs are altered, which disrupt cyclic nucleotide levels and promote cardiac dysfunction. Given that the morbidity and mortality associated with HF are extremely high, novel therapies are urgently needed. Herein, the role of PDEs in HF pathophysiology and their therapeutic potential is reviewed. Attention is given to PDEs 1-5, and other PDEs are briefly considered. After assessing the role of each PDE in cardiac physiology, the evidence from pre-clinical models and patients that altered PDE signalling contributes to the HF phenotype is examined. The potential of pharmacologically harnessing PDEs for therapeutic gain is considered.

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Phosphodiesterase type 3A (PDE3A), but not type 3B (PDE3B), contributes to the adverse cardiac remodeling induced by pressure overload

Cited by 17 publications

References 55 publications

Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress

Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress

Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiac hypertrophy and heart failure

Cardiac Cyclic Nucleotide Phosphodiesterases: Roles and Therapeutic Potential in Heart Failure

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