Ventricular Phosphodiesterase-5 Expression Is Increased in Patients With Advanced Heart Failure and Contributes to Adverse Ventricular Remodeling After Myocardial Infarction in Mice
View/ Open
nihms126491.pdf (5.033Mb)
Access Status
Full text of the requested work is not available in DASH at this time ("restricted access"). For more information on restricted deposits, see our FAQ.Author
Pokreisz, Peter
Bito, Virginie
Van den Bergh, An
Lenaerts, Ilse
Busch, Cornelius
Marsboom, Glenn
Gheysens, Olivier
Vermeersch, Pieter
Biesmans, Liesbeth
Liu, Xiaoshun
Gillijns, Hilde
Pellens, Marijke
Van Lommel, Alfons
Schoonjans, Luc
Vanhaecke, Johan
Verbeken, Erik
Sipido, Karin
Herijgers, Paul
Janssens, Stefan P.
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.1161/CIRCULATIONAHA.108.822072Metadata
Show full item recordCitation
Pokreisz, P., S. Vandenwijngaert, V. Bito, A. Van den Bergh, I. Lenaerts, C. Busch, G. Marsboom, et al. 2009. “Ventricular Phosphodiesterase-5 Expression Is Increased in Patients With Advanced Heart Failure and Contributes to Adverse Ventricular Remodeling After Myocardial Infarction in Mice.” Circulation 119 (3) (January 12): 408–416. doi:10.1161/circulationaha.108.822072. Open manuscript version available here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791110/Abstract
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.
Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791110/Citable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:14229238
Collections
- HMS Scholarly Articles [17922]
Contact administrator regarding this item (to report mistakes or request changes)