title: Pressure-overload magnitude-dependence of the anti-hypertrophic efficacy of PDE5A inhibition.
abstract: Increased myocardial cGMP, achieved by enhancing cyclase activity or impeding cGMP hydrolysis by phosphodiesterase type-5 (PDE5A), suppresses cellular and whole organ hypertrophy. The efficacy of the latter also requires cyclase stimulation and may depend upon co-activation of maladaptive signaling suppressible by cGMP-stimulated kinase (cGK-1). Thus, PDE5A inhibitors could paradoxically be more effective against higher than lower magnitudes of pressure-overload stress. To test this, mice were subjected to severe or moderate trans-aortic constriction (sTAC, mTAC) for 6 wks +/-co-treatment with oral sildenafil (SIL 200 mg/kg/d). LV mass (LVM) rose 130% after 3-wks sTAC and SIL blunted this by 50%. With mTAC, LVM rose 56% at 3 wks but was unaffected by SIL, whereas a 90% increase in LVM after 6 wks was suppressed by SIL. SIL minimally altered LV function and remodeling with mTAC until later stages that stimulated more hypertrophy and remodeling. SIL stimulated cGK-1 activity similarly at 3 and 6 wks of mTAC. However, pathologic stress signaling (e.g. calcineurin, ERK-MAPkinase) was little activated after 3-wk mTAC, unlike sTAC or later stage mTAC when activity increased and SIL suppressed it. With modest hypertrophy (3-wk mTAC), GSK3beta and Akt phosphorylation were unaltered but SIL enhanced it. However, with more severe hypertrophy (6-wk mTAC and 3-wk sTAC), both kinases were highly phosphorylated and SIL treatment reduced it. Thus, PDE5A-inhibition counters cardiac pressure-overload stress remodeling more effectively at higher than lower magnitude stress, coupled to pathologic signaling activation targetable by cGK-1 stimulation. Such regulation could impact responses of varying disease models to PDE5A inhibitors.
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, MD 21287, USA.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nagayama
authors.forename: Steven
authors.initials: S
authors.lastname: Hsu
authors.forename: Manling
authors.initials: M
authors.lastname: Zhang
authors.forename: Norimichi
authors.initials: N
authors.lastname: Koitabashi
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Gabrielson
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology* / Q000473:pathology*; D003251:Constriction, Pathologic / Q000201:enzymology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006984:Hypertrophy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058986:Phosphodiesterase 5 Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011312:Pressure; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D013312:Stress, Physiological / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology; D013997:Time Factors
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D017869:Cyclic GMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse