Published Online
on January 12, 2009

A more recent version of this article appeared on January 27, 2009

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Submitted on September 15, 2008
Accepted on November 6, 2008

Ventricular Phosphodiesterase-5 Expression Is Increased in Patients With Advanced Heart Failure and Contributes to Adverse Ventricular Remodeling After Myocardial Infarction in Mice

Peter Pokreisz PhD, Sara Vandenwijngaert MS, Virginie Bito PhD, An Van den Bergh PhD, Ilse Lenaerts MS, Cornelius Busch MD, Glenn Marsboom PhD, Olivier Gheysens MD, Pieter Vermeersch MD, Liesbeth Biesmans MS, Xiaoshun Liu MD, PhD, Hilde Gillijns BS, Marijke Pellens BS, Alfons Van Lommel PhD, Emmanuel Buys PhD, Luc Schoonjans PhD, Johan Vanhaecke MD, PhD, Erik Verbeken MD, PhD, Karin Sipido MD, PhD, Paul Herijgers MD, PhD, Kenneth D. Bloch MD, and Stefan P. Janssens MD, PhD^*

From the Vesalius Research Center (P.P., S.V., G.M., P.V., X.L., H.G., M.P., L.S., S.P.J.), VIB (Flanders Institute for Biotechnology), Leuven, Belgium; Division of Clinical Cardiology (J.V., S.P.J.), Experimental Cardiac Surgery (A.V.d.B., P.H.), Experimental Cardiology (P.P., V.B., I.L., L.B., K.S.), Imaging and Cardiovascular Dynamics, Department of Cardiovascular Medicine (O.G.), and Department of Medical Diagnostic Sciences (A.V.L., E.V.), KU Leuven, Leuven, Belgium; and Cardiovascular Research Center and Department of Anesthesia and Critical Care (C.B., E.B., K.D.B.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: stefan.janssens{at}med.kuleuven.be.

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).

Methods and 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 µL, 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.

Key words: phosphodiesterase-5 • cyclic GMP • myocardial infarction • heart failure

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Circulation 2009 119: 359-361. [Extract] [Full Text]

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