Myocardial remodeling is controlled by myocyte-targeted gene regulation of phosphodiesterase type 5.
OBJECTIVE
we tested the hypothesis that bi-directional, gene-targeted regulation of cardiomyocyte cyclic guanosine monophosphate-selective phosphodiesterase type 5 (PDE5) influences maladaptive remodeling in hearts subjected to sustained pressure overload.


BACKGROUND
PDE5 expression is up-regulated in human hypertrophied and failing hearts, and its inhibition (e.g., by sildenafil) stimulates protein kinase G activity, suppressing and reversing maladaptive hypertrophy, fibrosis, and contractile dysfunction. Sildenafil is currently being clinically tested for the treatment of heart failure. However, researchers of new studies have questioned the role of myocyte PDE5 and protein kinase G (PKG) to this process, proposing alternative targets and mechanisms.


METHODS
mice with doxycycline-controllable myocyte-specific PDE5 gene expression were generated (medium transgenic [TG] and high TG expression lines) and subjected to sustained pressure overload.


RESULTS
Rest myocyte and heart function, histology, and molecular profiling were normal in both TG lines versus controls at 2 months of age. However, upon exposure to pressure overload (aortic banding), TG hearts developed more eccentric remodeling, maladaptive molecular signaling, depressed function, and amplified fibrosis with up-regulation of tissue growth factor signaling pathways. PKG activation was inhibited in TG myocytes versus controls. After establishing a severe cardiomyopathic state, high-TG mice received doxycycline to suppress PDE5 expression/activity only in myocytes. This in turn enhanced PKG activity and reversed all previously amplified maladaptive responses, despite sustained pressure overload. Sildenafil was also effective in this regard.


CONCLUSIONS
these data strongly support a primary role of myocyte PDE5 regulation to myocardial pathobiology and PDE5 targeting therapy in vivo and reveal a novel mechanism of myocyte-orchestrated extracellular matrix remodeling via PDE5/cyclic guanosine monophosphate-PKG regulatory pathways.
Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Manling
M
Zhang
Eiki
E
Takimoto
Steven
S
Hsu
Dong I
DI
Lee
Takahiro
T
Nagayama
Thomas
T
Danner
Norimichi
N
Koitabashi
Andreas S
AS
Barth
Djahida
D
Bedja
Kathleen L
KL
Gabrielson
Yibin
Y
Wang
David A
DA
Kass
D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D009000:Monocytes / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D015398:Signal Transduction; D020257:Ventricular Remodeling / Q000235:genetics*
D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse