Ventricular Phosphodiesterase-5 Expression Is Increased in Patients With Advanced Heart Failure and Contributes to Adverse Ventricular Remodeling After Myocardial Infarction in Mice
| Autor: | Stefan Janssens, Xiaoshun Liu, Alfons Van Lommel, An Van Den Bergh, Paul Herijgers, Emmanuel S. Buys, Liesbeth Biesmans, Luc Schoonjans, Hilde Gillijns, Karin R. Sipido, Johan Vanhaecke, Sara Vandenwijngaert, Marijke Pellens, Virginie Bito, Cornelius J. Busch, Olivier Gheysens, Pieter Vermeersch, Erik Verbeken, Peter Pokreisz, Kenneth D. Bloch, Glenn Marsboom, Ilse Lenaerts |
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| Rok vydání: | 2009 |
| Předmět: |
medicine.medical_specialty
Heart Ventricles Immunoelectron microscopy Myocardial Infarction Mice Transgenic Article Gene Expression Regulation Enzymologic Muscle hypertrophy Mice Right ventricular hypertrophy Physiology (medical) Internal medicine Animals Humans Medicine Myocardial infarction Ventricular remodeling Cyclic Nucleotide Phosphodiesterases Type 5 Heart Failure Ischemic cardiomyopathy CGMP binding Ventricular Remodeling business.industry Myocardium medicine.disease Mice Inbred C57BL Heart failure Cardiology Cardiology and Cardiovascular Medicine business |
| Zdroj: | Circulation. 119:408-416 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circulationaha.108.822072 |
| Popis: | 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 P 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. |
| Databáze: | OpenAIRE |
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