Abstract
Heart failure (HF) is characterized by poor survival, a loss of catecholamine reserve and cellular structural remodeling in the form of disorganization and loss of the transverse tubule network. Indeed, survival rates for HF are worse than many common cancers and have not improved over time. Tadalafil is a clinically relevant drug that blocks phosphodiesterase 5 with high specificity and is used to treat erectile dysfunction. Using a sheep model of advanced HF, we show that tadalafil treatment improves contractile function, reverses transverse tubule loss, restores calcium transient amplitude and the heart’s response to catecholamines. Accompanying these effects, tadalafil treatment normalized BNP mRNA and prevented development of subjective signs of HF. These effects were independent of changes in myocardial cGMP content and were associated with upregulation of both monomeric and dimerized forms of protein kinase G and of the cGMP hydrolyzing phosphodiesterases 2 and 3. We propose that the molecular switch for the loss of transverse tubules in HF and their restoration following tadalafil treatment involves the BAR domain protein Amphiphysin II (BIN1) and the restoration of catecholamine sensitivity is through reductions in G-protein receptor kinase 2, protein phosphatase 1 and protein phosphatase 2 A abundance following phosphodiesterase 5 inhibition.
Highlights
In addition to the classical cAMP-dependent process, the myocardial response to catecholamine stimulation is regulated by the cGMP-Protein kinase G (PKG) signaling axis consisting of the β3-AR/soluble guanylate cyclase and www.nature.com/scientificreports/
The main findings of the present study investigating the impact of chronic PDE5 inhibition on cardiac function and structure in Heart failure (HF) are threefold: i) PDE5 inhibition improves indices of cardiac contractility and restores systolic calcium and catecholamine responsiveness; ii) t-tubule density is reduced in HF and fully restored to control levels by PDE5 inhibition and, iii) changes in expression of the putative t-tubule regulator Amphiphysin II (AmpII) are correlated with changes in t-tubule density and AmpII drives de novo tubule formation in ventricular myocytes
In this study we demonstrate that PDE5 inhibition reverses rather than prevents the HF-dependent changes in cellular structure and catecholamine responsiveness as both the reduction in TT density and loss of catecholamine responsiveness are already present before PDE5 inhibition is commenced
Summary
In addition to the classical cAMP-dependent process, the myocardial response to catecholamine stimulation is regulated by the cGMP-PKG signaling axis consisting of the β3-AR/soluble guanylate cyclase (sGC) and www.nature.com/scientificreports/. In the ‘positive’ studies the extent of disease progression to symptomatic HF is unclear and data on survival outcomes is generally missing Given these considerations, the hypothesis examined is that PDE5 inhibition is beneficial in systolic HF through restoration of catecholamine responsiveness. The primary aim of the present study was to determine if PDE5 inhibitor treatment, instigated at an advanced disease stage once contractile dysfunction and attenuated catecholamine responsiveness are established, is capable of reversing these effects. PDE5 inhibition restored the amplitude of the systolic calcium transient to control levels These changes were associated with a restoration of TT density but β-AR abundance (β1 and β2) remained unaltered in HF and following tadalafil treatment. We found that tadalafil treatment reversed myocardial changes in BNP expression and that this was associated with the prevention of the development of subjective HF symptoms
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
