Phosphodiesterase-5A (PDESA) is localized to the endothelial caveolae and modulates NOS3 activity

Milena A GEBSKA; Blake K STEVENSON; Travis D STRONG; Carol A COOKE; Hazim EL-HADDAD; Rubin M TUDER; Dan E BERKOWITZ; Hunter C CHAMPION; Anna R HEMNES; Trinity J BIVALACQUA; Azeb HAILE; Geoffrey G HESKETH; Christopher I MURRAY; Ari L ZAIMAN; Marc K HALUSHKA; Nispa KRONGKAEW

doi:10.1093/cvr/cvq410

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Phosphodiesterase-5A (PDESA) is localized to the endothelial caveolae and modulates NOS3 activity

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Phosphodiesterase-5A (PDESA) is localized to the endothelial caveolae and modulates NOS3 activity

Milena A GEBSKA, Blake K STEVENSON, Travis D STRONG, Carol A COOKE, Hazim EL-HADDAD, Rubin M TUDER, Dan E BERKOWITZ, Hunter C CHAMPION, Anna R HEMNES, Trinity J BIVALACQUA, …

Cardiovascular research, Vol.90(2), pp.353-363

2011

DOI: 10.1093/cvr/cvq410

PMCID: PMC3078797

PMID: 21421555

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Abstract

Aims: It has been well demonstrated that phosphodiesterase-5A (PDE5A) is expressed in smooth muscle cells and plays an important role in regulation of vascular tone. The role of endothelial PDE5A, however, has not been yet characterized. The present study was undertaken to determine the presence, localization, and potential physiologic significance of PDE5A within vascular endothelial cells. Methods and results: We demonstrate primary location of human, mouse, and bovine endothelial PDE5A at or near caveolae. We found that the spatial localization of PDE5A at the level of caveolin-rich lipid rafts allows for a feedback loop between endothelial PDE5A and nitric oxide synthase (NOS3). Treatment of human endothelium with PDE5A inhibitors resulted in a significant increase in NOS3 activity, whereas overexpression of PDE5A using an adenoviral vector, both in vivo and in cell culture, resulted in decreased NOS3 activity and endothelium-dependent vasodilation. The molecular mechanism responsible for these interactions is primarily regulated by cGMP-dependent second messenger. PDE5A overexpression also resulted in a significant decrease in protein kinase 1 (PKG1) activity. Overexpression of PKG1 rapidly activated NOS3, whereas silencing of the PKG1 gene with siRNA inhibited both NOS3 phosphorylation (S1179) and activity, indicating a novel role for PKG1 in direct regulation of NOS3. Conclusion: Our data collectively suggest another target for PDE5A inhibition in endothelial dysfunction and provide another physiologic significance for PDE5A in the modulation of endothelial-dependent flow-mediated vasodilation. Using both in vitro and in vivo models, as well as human data, we show that inhibition of endothelial PDE5A improves endothelial function.

Cardiology. Vascular system

Biological and medical sciences

Medical sciences

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Title: Subtitle: Phosphodiesterase-5A (PDESA) is localized to the endothelial caveolae and modulates NOS3 activity
Creators: Milena A GEBSKA - Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Rutland Avenue, Baltimore, MD 21205, United States
Blake K STEVENSON - Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Rutland Avenue, Baltimore, MD 21205, United States
Travis D STRONG - Division of Pulmonary, Allergy, and Critical Care Medicine, Johns Hopkins University School of Medicine, Rutland Avenue, Baltimore, MD 21205, United States
Carol A COOKE - Department of Cell Biology and Imaging, Johns Hopkins University School of Medicine, 725 N. Wolfe St, Baltimore, MD 21205, United States
Hazim EL-HADDAD - Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Rutland Avenue, Baltimore, MD 21205, United States
Rubin M TUDER - Program in Translational Lung Research, University of Colorado Denver, 13001 E. 17th Place, Aurora, CO 80045, United States
Dan E BERKOWITZ - Department of Anaesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, 600 N. Wolfe St., Baltimore, MD 21287, United States
Hunter C CHAMPION - Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Rutland Avenue, Baltimore, MD 21205, United States
Anna R HEMNES - Division of Pulmonary, Allergy, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States
Trinity J BIVALACQUA - The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins Medical Institutions, 600 North Wolfe St., Marburg 143, Baltimore, MD 21287, United States
Azeb HAILE - Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Rutland Avenue, Baltimore, MD 21205, United States
Geoffrey G HESKETH - Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Rutland Avenue, Baltimore, MD 21205, United States
Christopher I MURRAY - Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Rutland Avenue, Baltimore, MD 21205, United States
Ari L ZAIMAN - Division of Pulmonary, Allergy, and Critical Care Medicine, Johns Hopkins University School of Medicine, Rutland Avenue, Baltimore, MD 21205, United States
Marc K HALUSHKA - Department of Pathology, Department of Medicine, Johns Hopkins Medical Institutions, Ross RM 632L, 720 Rutland Avenue, Baltimore, MD 21205, United States
Nispa KRONGKAEW - Department of Pathology, Department of Medicine, Johns Hopkins Medical Institutions, Ross RM 632L, 720 Rutland Avenue, Baltimore, MD 21205, United States
Resource Type: Journal article
Publication Details: Cardiovascular research, Vol.90(2), pp.353-363
Publisher: Oxford University Press
DOI: 10.1093/cvr/cvq410
PMID: 21421555
PMCID: PMC3078797
ISSN: 0008-6363
eISSN: 1755-3245
Language: English
Date published: 2011
Academic Unit: Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984094490302771

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