Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice.
BACKGROUND
Ventricular expression of phosphodiesterase-5 (PDE5), an enzyme responsible for cGMP catabolism, is increased in human right ventricular hypertrophy, but its role in left ventricular (LV) failure remains incompletely understood. We therefore measured LV PDE5 expression in patients with advanced systolic heart failure and characterized LV remodeling after myocardial infarction in transgenic mice with cardiomyocyte-specific overexpression of PDE5 (PDE5-TG).


RESULTS
Immunoblot and immunohistochemistry techniques revealed that PDE5 expression was greater in explanted LVs from patients with dilated and ischemic cardiomyopathy than in control hearts. To evaluate the impact of increased ventricular PDE5 levels on cardiac function, PDE5-TG mice were generated. Confocal and immunoelectron microscopy revealed increased PDE5 expression in cardiomyocytes, predominantly localized to Z-bands. At baseline, myocardial cGMP levels, cell shortening, and calcium handling in isolated cardiomyocytes and LV hemodynamic measurements were similar in PDE5-TG and wild-type littermates. Ten days after myocardial infarction, LV cGMP levels had increased to a greater extent in wild-type mice than in PDE5-TG mice (P<0.05). Ten weeks after myocardial infarction, LV end-systolic and end-diastolic volumes were larger in PDE5-TG than in wild-type mice (57+/-5 versus 39+/-4 and 65+/-6 versus 48+/-4 muL, respectively; P<0.01 for both). LV systolic dysfunction and diastolic dysfunction were more marked in PDE5-TG than in wild-type mice, associated with enhanced hypertrophy and reduced contractile function in isolated cardiomyocytes from remote myocardium.


CONCLUSIONS
Increased PDE5 expression predisposes mice to adverse LV remodeling after myocardial infarction. Increased myocardial PDE5 expression in patients with advanced cardiomyopathy may contribute to the development of heart failure and represents an important therapeutic target.
Pokreisz
Peter
P
Vesalius Research Center, Flanders Institute for Biotechnology, Leuven, Belgium.
Vandenwijngaert
Sara
S
Bito
Virginie
V
Van den Bergh
An
A
Lenaerts
Ilse
I
Busch
Cornelius
C
Marsboom
Glenn
G
Gheysens
Olivier
O
Vermeersch
Pieter
P
Biesmans
Liesbeth
L
Liu
Xiaoshun
X
Gillijns
Hilde
H
Pellens
Marijke
M
Van Lommel
Alfons
A
Buys
Emmanuel
E
Schoonjans
Luc
L
Vanhaecke
Johan
J
Verbeken
Erik
E
Sipido
Karin
K
Herijgers
Paul
P
Bloch
Kenneth D
KD
Janssens
Stefan P
SP
D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006333:Heart Failure / Q000201:enzymology* / Q000503:physiopathology; D006352:Heart Ventricles / Q000201:enzymology / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000201:enzymology* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D020257:Ventricular Remodeling / Q000235:genetics*
D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C517382:Pde5a protein, mouse