The Emperor's New Clothes: PDE5 and the Heart

Degen, Chantal Vanessa; Bishu, Kalkidan; Zakeri, Rosita; Ogut, Ozgur; Redfield, Margaret M.; Brozovich, Frank V.

doi:10.1371/journal.pone.0118664

Cited by 33 publications

(33 citation statements)

References 43 publications

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“…PDE5 upregulation in HFrEF was reported by multiple 96,97 but not all 98 laboratories. Data in HFpEF did not support a similar elevation 23 , and two PDE5-inhibitor trials in HFpEF yielded a neutral outcome 99,100 .…”

Section: Phenotypic Treatment Strategymentioning

confidence: 93%

Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction

Shah¹,

et al. 2016

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Heart failure (HF) with preserved ejection fraction (EF) (HFpEF) accounts for 50% of HF cases and its prevalence relative to HF with reduced EF (HFrEF) continues to rise. In contrast to HFrEF, large trials testing neurohumoral inhibition in HFpEF failed to reach a positive outcome. This failure was recently attributed to distinct systemic and myocardial signaling in HFpEF and to diversity of HFpEF phenotypes. In this review, a HFpEF treatment strategy is proposed which addresses HFpEF-specific signaling and phenotypic diversity. In HFpEF, extracardiac comorbidities such as metabolic risk, arterial hypertension and renal insufficiency drive left ventricular (LV) remodeling and dysfunction through systemic inflammation and coronary microvascular endothelial dysfunction. The latter affects LV diastolic dysfunction through macrophage infiltration resulting in interstitial fibrosis and through altered paracrine signaling to cardiomyocytes, which become hypertrophied and stiff because of low nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). Systemic inflammation also affects other organs such as lungs, skeletal muscle and kidneys leading respectively to pulmonary hypertension, muscle weakness and sodium retention. Individual steps of these signaling cascades can be targeted by specific interventions: metabolic risk by caloric restriction, systemic inflammation by statins, pulmonary hypertension by phosphodiesterase (PDE) 5 inhibitors, muscle weakness by exercise training, sodium retention by diuretics and monitoring devices, myocardial NO bioavailability by inorganic nitrate-nitrite, myocardial cGMP content by neprilysin or PDE 9 inhibition and myocardial fibrosis by spironolactone. Because of phenotypic diversity in HFpEF, personalized therapeutic strategies are proposed, which are configured in a matrix with HFpEF presentations in the abscissa and HFpEF predispositions in the ordinate.

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Section: Phenotypic Treatment Strategymentioning

confidence: 93%

Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction

Shah¹,

et al. 2016

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“…There remains some controversy regarding PDE5A expression in the human heart, based primarily on differences in immunoblot data (Degen et al, 2015). As gene deletion models – even conditional ones - have not been successful, absolute proof of the role of normal PDE5A in the heart in vivo remains indirect.…”

Section: Pde5 and Dilated Cardiomyopathymentioning

confidence: 99%

Cardiac Phosphodiesterases and Their Modulation for Treating Heart Disease

Kim

Kass

2016

Handbook of Experimental Pharmacology

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An important hallmark of cardiac failure is abnormal second messenger signaling due to impaired synthesis and catabolism of adenosine 3’,5’-cyclic monophosphate (cAMP) and cyclic guanosine 3’,5’-cyclic monophosphate (cGMP). Their dysregulation, altered intracellular targeting, and blunted responsiveness to stimulating pathways all contribute to pathological remodeling, muscle dysfunction, reduced cell survival and metabolism, and other abnormalities. Therapeutic enhancement of either cyclic nucleotide can be achieved by stimulating their synthesis and/or by suppressing members of the family of cyclic nucleotide phosphodiesterases (PDEs). The heart expresses seven of the eleven major PDE sub-types - PDE1, 2, 3, 4, 5, 8, and 9. Their differential control over cAMP and cGMP signaling in various cell types, including cardiomyocytes, provides intriguing therapeutic opportunities to counter heart disease. This review examines the roles of these PDEs in the failing and hypertrophied heart, and summarizes experimental and clinical data that has explored the utility of targeted PDE inhibition.

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“…Together, the current data allow us to conclude that in the presence of amplified AT 1 R signal transduction in murine CMs and hypertrophic heart disease, potentially beneficial effects of cGMP do not involve SIL/PDE5 directly in these cells (Lukowski et al, 2010Mokni et al, 2010;Degen et al, 2015).…”

Section: Resultsmentioning

confidence: 54%

“…Exposure of gene-targeted mice that lack cGKI in all non-SMCs with a hypertensive dose of Ang II demonstrated antifibrotic rather than antihypertrophic modes of action for SIL/PDE5/cGMP/ cGKI signaling (Patrucco et al, 2014). It seems reasonable that cardiac fibroblasts are the primary target of SIL, as they display the full repertoire for the cross-talk between PDE5/ cGMP/cGKI and AT 1 R, and the presence of PDE5 in murine CMs (Lukowski et al, 2010) and heart (Degen et al, 2015) was recently challenged. Increased cardiac and aortic cGMP concentrations in the presence of SIL (Fig.…”

Section: Discussionmentioning

confidence: 99%

Sildenafil Does Not Prevent Heart Hypertrophy and Fibrosis Induced by Cardiomyocyte Angiotensin II Type 1 Receptor Signaling

Straubinger

Schöttle

Bork

et al. 2015

J Pharmacol Exp Ther

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Analyses of several mouse models imply that the phosphodiesterase 5 (PDE5) inhibitor sildenafil (SIL), via increasing cGMP, affords protection against angiotensin II (Ang II)-stimulated cardiac remodeling. However, it is unclear which cell types are involved in these beneficial effects, because Ang II may exert its adverse effects by modulating multiple renovascular and cardiac functions via Ang II type 1 receptors (AT 1 Rs). To test the hypothesis that SIL/cGMP inhibit cardiac stress provoked by amplified Ang II/AT 1 R directly in cardiomyocytes (CMs), we studied transgenic mice with CM-specific overexpression of the AT 1 R under the control of the a-myosin heavy chain promoter (aMHC-AT 1 R tg/1 ). The extent of cardiac growth was assessed in the absence or presence of SIL and defined by referring changes in heart weight to body weight or tibia length. Hypertrophic marker genes, extracellular matrix-regulating factors, and expression patterns of fibrosis markers were examined in aMHC-AT 1 R tg/1 ventricles (with or without SIL) and corroborated by investigating different components of the natriuretic peptide/PDE5/cGMP pathway as well as cardiac functions. cGMP levels in heart lysates and intact CMs were measured by competitive immunoassays and Förster resonance energy transfer. We found higher cardiac and CM cGMP levels and upregulation of the cGMP-dependent protein kinase type I with AT 1 R overexpression. However, even a prolonged SIL treatment regimen did not limit the progressive CM growth, fibrosis, or decline in cardiac functions in the aMHC-AT 1 R tg/1 model, suggesting that SIL does not interfere with the pathogenic actions of amplified AT 1 R signaling in CMs. Hence, the cardiac/ noncardiac cells involved in the cross-talk between SIL-sensitive PDE activity and Ang II/AT 1 R still need to be identified.

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The Emperor's New Clothes: PDE5 and the Heart

Cited by 33 publications

References 43 publications

Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction

Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction

Cardiac Phosphodiesterases and Their Modulation for Treating Heart Disease

Sildenafil Does Not Prevent Heart Hypertrophy and Fibrosis Induced by Cardiomyocyte Angiotensin II Type 1 Receptor Signaling

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