Phosphodiesterase 2 inhibition preferentially promotes NO/guanylyl cyclase/cGMP signaling to reverse the development of heart failure.

Proceedings of the National Academy of Sciences of the United States of America
Reshma S BaligaAdrian J Hobbs

Abstract

Heart failure (HF) is a shared manifestation of several cardiovascular pathologies, including hypertension and myocardial infarction, and a limited repertoire of treatment modalities entails that the associated morbidity and mortality remain high. Impaired nitric oxide (NO)/guanylyl cyclase (GC)/cyclic guanosine-3',5'-monophosphate (cGMP) signaling, underpinned, in part, by up-regulation of cyclic nucleotide-hydrolyzing phosphodiesterase (PDE) isozymes, contributes to the pathogenesis of HF, and interventions targeted to enhancing cGMP have proven effective in preclinical models and patients. Numerous PDE isozymes coordinate the regulation of cardiac cGMP in the context of HF; PDE2 expression and activity are up-regulated in experimental and human HF, but a well-defined role for this isoform in pathogenesis has yet to be established, certainly in terms of cGMP signaling. Herein, using a selective pharmacological inhibitor of PDE2, BAY 60-7550, and transgenic mice lacking either NO-sensitive GC-1α (GC-1α-/-) or natriuretic peptide-responsive GC-A (GC-A-/-), we demonstrate that the blockade of PDE2 promotes cGMP signaling to offset the pathogenesis of experimental HF (induced by pressure overload or sympathetic hyperactivation), ...Continue Reading

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Citations

Oct 12, 2018·The Journal of Physiology·E N Bardsley, D J Paterson
Oct 28, 2019·Journal of Cardiovascular Pharmacology·Brittany Dunkerly-Eyring, David A Kass
Sep 23, 2020·Expert Opinion on Drug Discovery·Si Chen, Chen Yan
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Jan 24, 2021·Cardiovascular Research·Yuening LiuZhaokang Cheng
Jan 12, 2020·Communications Biology·Gaia CalameraKjetil Wessel Andressen
Nov 7, 2020·International Journal of Molecular Sciences·Agnieszka Kilanowska, Agnieszka Ziółkowska
Jun 3, 2021·International Journal of Molecular Sciences·Michael WagnerSusanne Kämmerer
May 16, 2021·British Journal of Pharmacology·Robert LukowskiPeter Ruth

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Methods Mentioned

BETA
transgenic
biopsies
PCR
Assay
Fluorescence

Software Mentioned

GraphPad
ImageJ
GraphPad Prism

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