The long and winding road of designing phosphodiesterase inhibitors for the treatment of heart failure

Nadur, Nathália Fonseca; Azevedo, Luciana Luiz de; Caruso, Lucas; Graebin, Cedric Stephan; Lacerda, Renata Barbosa; Kümmerle, Arthur Eugen

doi:10.1016/j.ejmech.2020.113123

Cited by 21 publications

(8 citation statements)

References 240 publications

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“…Growing preclinical studies have reported that PDE5 inhibitors play a protective role against cardiovascular diseases, such as heart failure, MI, ischemia-induced ventricular arrhythmias, myocardial hypertrophy and so on (4)(5)(6). Several clinical trials have demonstrated the benefits of PDE5 inhibitors in patients with heart failure, while the effect on ischemic heart disease is still uncertain (28). A number of observational studies have reported the protective effect of PDE5 inhibitors on ischemic heart disease (29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

Combination of QTL and GWAS to uncover the role of phosphodiesterases in ischemic heart disease

Xiao,

Gao,

Wei

et al. 2023

Preprint

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Background: Phosphodiesterases (PDEs) are regarded as important therapeutic targets for multiple diseases, and the cardiovascular benefits of several PDE inhibitors have received extensive interests. Objectives: To explore the relationship between genetically-predicted PDEs and ischemia heart disease via drug target Mendelian Randomization (MR) approach. Methods: The expression of genes encoding PDEs was used to proxy the level of PDEs, and available quantitative trait loci of gene expression and DNA methylation (eQTLs and mQTLs) for each target gene were identified as the genetic instruments. Coronary heart disease (CHD) and myocardial infarction (MI) were the outcomes. Summary-data-based MR method was used to generate the estimates and two-step MR analysis was applied to investigate the mediation of metabolic traits. Results: MR analyses identified two types of PDEs, PDE5 and PDE8, genetically-predicted expression in blood of the encoded genes was significantly associated with the risk of CHD (ORPDE5A=1.22,95% CI=1.06-1.40; ORPDE8A=1.26,95% CI=1.07-1.49) and MI (ORPDE5A=1.27,95% CI=1.09-1.48; ORPDE8A=1.24,95% CI=1.04-1.48). Especially, the highest expression of PDE5A was observed in artery aorta, which was also positively related to CHD (OR=1.17,95% CI=1.05-1.32) and MI (OR=1.15,95% CI=1.02-1.30). Besides, the methylation level of 12 CpG sites showed a relation with CHD or MI via affecting PDE5A expression. The observed association between PDE5A expression and outcomes were partly mediated by blood pressure and LDL cholesterol, and the association with MI were mostly mediated by CHD (Proportion-mediated: 78.84%). Conclusions: This study provided genetic evidence about the protective role of PDE5 inhibition against ischemic heart disease, especially in preventing patients with CHD from developing MI.

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Section: Discussionmentioning

confidence: 99%

Combination of QTL and GWAS to uncover the role of phosphodiesterases in ischemic heart disease

Xiao,

Gao,

Wei

et al. 2023

Preprint

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“…So far, little is known about the pharmacology and implicated application of the CNPase-2′,3′-cyclic nucleotide metabolic system. In contrast, therapeutic approaches based on the 3′,5′-cGMP/cAMP system, which give rise to drugs that block specific phosphodiesterases (PDEs), are still attracting great interest in the scientific research community, clinical and pharmaceutical industries [ 16 ]. However, phosphodiesterase-5 inhibition is not beneficial for heart failure patients with a preserved ejection fraction [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

CNPase, a 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy Production

Tan

Wang

et al. 2021

IJMS

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Heart failure is the end-stage of all cardiovascular diseases with a ~25% 5-year survival rate, and insufficient mitochondrial energy production to meet myocardial demand is the hallmark of heart failure. Mitochondrial components involved in the regulation of ATP production remain to be fully elucidated. Recently, roles of 2′,3′-cyclic nucleotide-3′-phosphodiesterase (CNPase) in the pathophysiological processes of heart diseases have emerged, implicated by evidence that mitochondrial CNPase proteins are associated with mitochondrial integrity under metabolic stress. In this study, a zebrafish heart failure model was established, by employing antisense morpholino oligonucleotides and the CRISPR-Cas9 gene-editing system, which recapitulates heart failure phenotypes including heart dysfunction, pericardial edema, ventricular enlargement, bradycardia, and premature death. The translational implications of CNPase in the pathophysiological process of heart failure were tested in a pressure overload-induced heart hypertrophy model, which was carried out in rats through transverse abdominal aorta constriction (TAAC). AAV9-mediated myocardial delivery of CNPase mitigated the hypertrophic response through the specific hydrolysis of 2′-3′-cyclic nucleotides, supported by the decrease of cardiac hypertrophy and fibrosis, the integrity of mitochondrial ultrastructure, and indicators of heart contractility in the AAV9-TAAC group. Finally, the biometrics of a mitochondrial respiration assay carried out on a Seahorse cellular energy analyzer demonstrated that CNPase protects mitochondrial respiration and ATP production from AngII-induced metabolic stress. In summary, this study provides mechanistic insights into CNPase-2′,3′-cyclic nucleotide metabolism that protects the heart from energy starvation and suggests novel therapeutic approaches to treat heart failure by targeting CNPase activity.

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“…Numerous pharmacotherapy trials have been conducted on patients with HFpEF, including the ones that target RV dysfunction ( Hoendermis et al, 2015 , Nadur et al, 2021 ). The most widely studied agents include phosphodiesterase (PDE) inhibitors, guanylate-cyclase stimulators, and inhaled sodium nitrite ( Bonderman et al, 2014 , Hoendermis et al, 2015 , Simon et al, 2016 , Zhang et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase inhibitor for heart failure with preserved ejection fraction: A systematic review and meta-analysis

Chen

Zhao

Xiao

et al. 2022

Saudi Pharmaceutical Journal

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The long and winding road of designing phosphodiesterase inhibitors for the treatment of heart failure

Cited by 21 publications

References 240 publications

Combination of QTL and GWAS to uncover the role of phosphodiesterases in ischemic heart disease

Combination of QTL and GWAS to uncover the role of phosphodiesterases in ischemic heart disease

CNPase, a 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy Production

Phosphodiesterase inhibitor for heart failure with preserved ejection fraction: A systematic review and meta-analysis

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