Phosphodiesterase Type 5

Kass, David A.; Champion, Hunter C.; Beavo, Joseph A.

doi:10.1161/circresaha.107.162511

Cited by 184 publications

(48 citation statements)

References 149 publications

(170 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PDE5A hydrolyzes cGMP primarily generated by NO-soluble guanylatecyclase; by blocking the enzyme, drugs such as sildenafil can augment cGMP and thus PKG activity in multiple organs relevant to HF. Experimental studies in mice with pressure-overload, 132 cytotoxicity from doxorubicin, 133 and myocardial infarction, 134-136 have shown benefits from chronic PDE5A inhibition. PDE5A inhibition also enhanced NP-stimulated pulmonary vasodilation in a canine HF model.…”

Section: Treatment Of Hfpef - a Brief History Of Neutral Trialsmentioning

confidence: 99%

Heart Failure With Preserved Ejection Fraction

Sharma

Kass

2014

Circulation Research

Self Cite

428

227

View full text Add to dashboard Cite

The clinical syndrome comprised of heart failure symptoms but with a left ventricular ejection fraction that is not diminished, e.g. heart failure with a preserved ejection fraction (HFpEF), is increasingly the predominant form of HF in the developed world, and soon to reach epidemic proportions. It remains among the most challenging of clinical syndromes for the practicing clinician and scientist alike, with a multitude of proposed mechanisms involving the heart and other organs and complex interplay with common co-morbidities. Importantly, its morbidity and mortality is on par with heart failure and a reduced ejection fraction, and as the list of failed treatments continues to grow, HFpEF clearly represents a major unmet medical need. The field is greatly in need of a more unified approach to its definition and view of the syndrome that engages integrative and reserve pathophysiology beyond that related to the heart alone. We need to reflect on prior treatment failures and the message this is providing, and re-direct our approaches likely with a paradigm shift in how the disease is viewed. Success will require interactions between clinicians, translational researchers, and basic physiologists. Here, we review recent translational and clinical research into HFpEF, give perspectives on its evolving demographics and epidemiology, the role of multi-organ deficiencies, potential mechanisms that involve the heart and other organs, clinical trials, and future directions.

show abstract

Section: Treatment Of Hfpef - a Brief History Of Neutral Trialsmentioning

confidence: 99%

Heart Failure With Preserved Ejection Fraction

Sharma

Kass

2014

Circulation Research

Self Cite

428

227

View full text Add to dashboard Cite

show abstract

“…It is interesting to consider that the activity of constitutively expressed isoforms of nitric oxide synthetase (eNOS and nNOS) are Ca 2+ -dependent and that Ca 2+ signalling is also well known to be compartmentalised, thereby providing a mechanism for local generation of NO, activation of sGC and cGMP production. cGMP levels are in turn regulated by cGMP-degrading PDEs (such as PDE5) that can be spatially confined[32] and subject to their specific regulatory mechanisms. Clearly, the integrated effects of these complex signalling networks are vast and spatial confinement of signalling events allows for a specific branch of the pathway to be appropriately activated, with other branches not being involved.…”

Section: Compartmentalised Camp Signallingmentioning

confidence: 99%

Spatial control of cAMP signalling in health and disease

Zaccolo

2011

Current Opinion in Pharmacology

View full text Add to dashboard Cite

The cyclic adenosine 3′,5′-monophosphate signalling pathway is now recognised to transduce signals in a compartmentalised manner such that individual stimuli only engage a subset of the pathway components that are physically constrained within defined subcellular locales, thus resulting in a precise functional outcome. As we are starting to appreciate the complexity of the spatial organisation and of the temporal regulation of this pathway, it is becoming clear that disruption of local signalling may lead to pathology and that local manipulation of cAMP signals may offer alternative approaches to treat disease.

show abstract

“…The major PDEs present in VSMCs are the cGMP-inhibited PDE (PDE3), the cAMP-specific PDE (PDE4), and the major cGMP-hydrolyzing enzyme PDE5 (Polson and Strada, 1996; Rose et al, 1997; Tilley and Maurice, 2002; Aizawa et al, 2003; Rybalkin et al, 2003; Kass et al, 2007a,b). Balloon angioplasty increases the expression and activity of PDE3 and PDE4 in VSMCs (Zhao et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterases Regulate BAY 41-2272-Induced VASP Phosphorylation in Vascular Smooth Muscle Cells

Adderley¹,

Joshi²,

Martin³

et al. 2012

Front. Pharmacol.

View full text Add to dashboard Cite

BAY 41-2272 (BAY), a stimulator of soluble guanylyl cyclase, increases cyclic nucleotides and inhibits proliferation of vascular smooth muscle cells (VSMCs). In this study, we elucidated mechanisms of action of BAY in its regulation of vasodilator-stimulated phosphoprotein (VASP) with an emphasis on VSMC phosphodiesterases (PDEs). BAY alone increased phosphorylation of VASPSer239 and VASPSer157, respective indicators of PKG and PKA signaling. IBMX, a non-selective inhibitor of PDEs, had no effect on BAY-induced phosphorylation at VASPSer239 but inhibited phosphorylation at VASPSer157. Selective inhibitors of PDE3 or PDE4 attenuated BAY-mediated increases at VASPSer239 and VASPSer157, whereas PDE5 inhibition potentiated BAY-mediated increases only at VASPSer157. In comparison, 8Br-cGMP increased phosphorylation at VASPSer239 and VASPSer157 which were not affected by selective PDE inhibitors. In the presence of 8Br-cAMP, inhibition of either PDE4 or PDE5 decreased VASPSer239 phosphorylation and inhibition of PDE3 increased phosphorylation at VASPSer239, while inhibition of PDE3 or PDE4 increased and PDE5 inhibition had no effect on VASPSer157 phosphorylation. These findings demonstrate that BAY operates via cAMP and cGMP along with regulation by PDEs to phosphorylate VASP in VSMCs and that the mechanism of action of BAY in VSMCs is different from that of direct cyclic nucleotide analogs with respect to VASP phosphorylation and the involvement of PDEs. Given a role for VASP as a critical cytoskeletal protein, these findings provide evidence for BAY as a regulator of VSMC growth and a potential therapeutic agent against vasculoproliferative disorders.

show abstract

Phosphodiesterase Type 5

Cited by 184 publications

References 149 publications

Heart Failure With Preserved Ejection Fraction

Heart Failure With Preserved Ejection Fraction

Spatial control of cAMP signalling in health and disease

Phosphodiesterases Regulate BAY 41-2272-Induced VASP Phosphorylation in Vascular Smooth Muscle Cells

Contact Info

Product

Resources

About