Ventricular Phosphodiesterase-5 Expression Is Increased in Patients With Advanced Heart Failure and Contributes to Adverse Ventricular Remodeling After Myocardial Infarction in Mice

Pokreisz, Péter; Vandenwijngaert, Sara; Bito, Virginie; Bergh, An Van Den; Lenaerts, Ilse; Busch, Cornelius; Marsboom, Glenn; Gheysens, Olivier; Vermeersch, Pieter; Biesmans, Liesbeth; Liu, Xiaoshun; Gillijns, Hilde; Pellens, Marijke; Buys, Emmanuel; Schoonjans, Luc; Vanhaecke, Johan; Verbeken, Erik; Sipido, Karin R.; Herijgers, Paul; Bloch, Kenneth D.; Janssens, Stefan

doi:10.1161/circulationaha.108.822072

Cited by 167 publications

(163 citation statements)

References 33 publications

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“…The cGMP‐PKG‐PDE5 signaling axis has been hypothesized to contribute to the pathophysiology of human HF 6, 50, 51, 52. However, this finding is not definitive in a setting of human HFpEF5, 9 where clinical data have failed to show benefits previously reported in multiple animal models 47, 50.…”

Section: Discussionmentioning

confidence: 96%

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Hiemstra

Lee

Chakir

et al. 2016

JAHA

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BackgroundCyclic guanosine monophosphate‐protein kinase G‐phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl‐peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function.Methods and ResultsWe assessed LV hypertrophy and function at the organ and cellular level in aortic‐banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end‐systolic pressure‐volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil‐treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening‐frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium‐retention capacity and Complex II‐dependent respiratory control, was present in both HF and tadalafil‐treated animals.ConclusionsBoth saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.

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Section: Discussionmentioning

confidence: 96%

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Hiemstra

Lee

Chakir

et al. 2016

JAHA

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“…It was recently reported that PDE-5 is up-regulated in patients with end-stage heart failure; however, 2 μM SIL was used for cGMP PDE assays as a test for PDE-5 activity (54). At this concentration, SIL can inhibit most of the cardiac PDE-1C activity (Fig.…”

Section: Discussionmentioning

confidence: 97%

Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes

Łukowski

Rybalkin

Loga

et al. 2010

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

137

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It has been suggested that cGMP kinase I (cGKI) dampens cardiac hypertrophy. We have compared the effect of isoproterenol (ISO) and transverse aortic constriction (TAC) on hypertrophy in WT [control (CTR)] mice, total cGKI-KO mice, and cGKIβ rescue mice (βRM) lacking cGKI specifically in cardiomyocytes (CMs). Infusion of ISO did not change the expression of cGKI in the hearts of CTR mice or βRM but raised the heart weight by ∼20% in both. An identical hypertrophic growth response was measured in CMs from CTR mice and βRM and in isolated adult CMs cultured with or without 1 μM ISO. In both genotypes, ISO infusion induced similar changes in the expression of hypertrophy-associated cardiac genes and significant elevation of serum atrial natriuretic peptide and total cardiac cGMP. No differences in cardiac hypertrophy were obtained by 7-day ISO infusion in 4-to 6-week-old conventional cGKI-KO and CTR mice. Furthermore, TAC-induced hypertrophy of CTR mice and βRM was not different and did not result in changes of the cGMP-hydrolyzing phosphodiesterase activities in hypertropic hearts or CMs. These results strongly suggest that cardiac myocyte cGKI does not affect the development of heart hypertrophy induced by pressure overload or chronic ISO infusion.cyclic nucleotides | phosphodiesterase | phosphorylation | transverse aortic constriction | sildenafil C linical studies and genetically modified mice have supported the notion that natriuretic peptides (NPs), the particulate guanylyl cyclase (GC)-A, and the second messenger cGMP can attenuate the development of pressure-or volume-induced cardiac hypertrophy and fibrosis (1). Disruption of the murine GC-A gene, the receptor for the cardiac "hormones" atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), results in salt-resistant elevation of blood pressure, cardiac fibrosis, and hypertrophy (2, 3). To a great extent, hypertrophy is independent of blood pressure elevation (4, 5) but is enhanced transverse aortic constriction (TAC) in the absence of GC-A (4). Further studies using cardiac muscle-specific deletion of GC-A confirmed that cardiac muscle hypertrophy is independent of changes in blood pressure (6). ANP, nitric oxide (NO) donors, and 8-Br-cGMP inhibited norepinephrine-induced hypertrophy of cardiac cells and fibroblasts (7,8).Although it is recognized that GC-A-deficient hearts exhibit marked hypertrophy with interstitial fibrosis (2, 9), deletion of ANP did not result in obvious hypertrophy and fibrosis (10). Other reports have indicated that ANP ablation in mice causes an accelerated susceptibility to hypertrophy induced by different stress stimuli (11,12). Obviously, ANP and BNP secreted by the cardiomyocytes (CMs) act as paracrine factors that exert antifibrotic effects in vivo and play a role as local regulators of ventricular remodeling. Furthermore, it has been shown that rats expressing a dominant-negative mutant of GC-B and having an attenuated cGMP response to C-natriuretic peptide and a normal response to ANP showed marked cardiac hyp...

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“…The rise in right ventricular contractility was due to an intrinsic myocardial effect because the pulmonary arteries were no longer present and could therefore not contribute to reduced right ventricular afterload. Pokreisz et al 47 confirmed that PDE-5 expression is greater in left ventricular myocardium of patients with HF compared to controls. To determine the impact of elevated PDE-5 levels in diseased left ventricles, the authors compared the effect of a myocardial infarction on mice with increased PDE-5 expression versus wild type.…”

Section: Mechanisms Of Pde-5 Inhibitors Improving Hfmentioning

confidence: 92%

Erectile dysfunction and heart failure: the role of phosphodiesterase type 5 inhibitors

Al-Ameri

Kloner

2009

Int J Impot Res

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The phosphodiesterase type 5 (PDE-5) inhibitors are effective in treating erectile dysfunction (ED). ED and heart failure (HF) share similar risk factors, and commonly present together. This association has led to questions ranging from the safety and efficacy of PDE-5 inhibitors in HF patients to a possible role for this class of medication to treat HF patients with or without ED. In addition to endothelial dysfunction, there are causes of ED specific to patients with HF including low exercise tolerance, depression and HF medications. Before treating HF patients with PDE-5 inhibitors, patients should be assessed for their risk of a cardiac event during sexual activity. PDE-5 inhibitors are safe and effective in treating ED in HF patients. An improvement in erectile function by PDE-5 inhibitors was associated with an improvement in quality of life and reduction in depression. Several studies demonstrated the effect of PDE-5 inhibitors on HF per se. PDE-5 inhibitors improved endothelial dysfunction, increased exercise tolerance, decreased pulmonary vascular resistance and pulmonary artery pressure, and increased cardiac index. Several mechanisms whereby PDE-5 inhibitors improve HF have been proposed. PDE-5 inhibitors already have a role in treating primary pulmonary hypertension; however additional studies are needed to determine if they will become a standard therapy for HF patients.

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Ventricular Phosphodiesterase-5 Expression Is Increased in Patients With Advanced Heart Failure and Contributes to Adverse Ventricular Remodeling After Myocardial Infarction in Mice

Cited by 167 publications

References 33 publications

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes

Erectile dysfunction and heart failure: the role of phosphodiesterase type 5 inhibitors

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