Document Detail

Novel peptide for attenuation of hypoxia-induced pulmonary hypertension via modulation of nitric oxide release and phosphodiesterase -5 activity.
MedLine Citation:
PMID:  22465621     Owner:  NLM     Status:  MEDLINE    
Pulmonary vascular endothelial nitric oxide (NO) synthase (eNOS)-derived NO is the major stimulant of cyclic guanosine 5'-monophosphate (cGMP) production and NO/cGMP-dependent vasorelaxation in the pulmonary circulation. We recently synthesized multiple peptides and reported that an eleven amino acid (SSWRRKRKESS) peptide (P1) but not scrambled P1 stimulated the catalytic activity but not expression of eNOS and causes NO/cGMP-dependent sustained vasorelaxation in isolated pulmonary artery (PA) segments and in lung perfusion models. Since cGMP levels can also be elevated by inhibition of phosphodiesterase type 5 (PDE-5), this study was designed to test the hypothesis that P1-mediated vesorelaxation is due to its unique dual action as NO-releasing PDE-5 inhibitor in the pulmonary circulation. Treatment of porcine PA endothelial cells (PAEC) with P1 caused time-dependent increase in intracellular NO release and inhibition of the catalytic activity of cGMP-specific PDE-5 but not PDE-5 protein expression leading to increased levels of cGMP. Acute hypoxia-induced PA vasoconstriction ex vivo and continuous telemetry monitoring of hypoxia (10% oxygen)-induced elevated PA pressure in freely moving rats were significantly restored by administration of P1. Chronic hypoxia (10% oxygen for 4 weeks)-induced alterations in PA perfusion pressure, right ventricular hypertrophy, and vascular remodeling were attenuated by P1 treatment. These results demonstrate the potential therapeutic effects of P1 to prevent and/or arrest the progression of hypoxia-induced PAH via NO/cGMP-dependent modulation of hemodynamic and vascular remodeling in the pulmonary circulation.
Hanbo Hu; Sergey Zharikov; Jawaharlal M Patel
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-03-20
Journal Detail:
Title:  Peptides     Volume:  35     ISSN:  1873-5169     ISO Abbreviation:  Peptides     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-04-16     Completed Date:  2012-08-07     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  8008690     Medline TA:  Peptides     Country:  United States    
Other Details:
Languages:  eng     Pagination:  78-85     Citation Subset:  IM    
Copyright Information:
Published by Elsevier Inc.
Department of Medicine, University of Florida, Gainesville, FL 32610-0225, United States.
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MeSH Terms
Amino Acid Sequence
Blood Pressure / drug effects
Cell Hypoxia
Cells, Cultured
Cyclic GMP / metabolism
Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism*
Endothelial Cells / drug effects,  metabolism
Hypertension, Pulmonary / drug therapy*
Hypertrophy, Right Ventricular / prevention & control
Lung / drug effects,  metabolism
Nitric Oxide / metabolism*
Nitric Oxide Synthase Type III / pharmacology*,  therapeutic use
Peptide Fragments / pharmacology*,  therapeutic use
Phosphodiesterase 5 Inhibitors / pharmacology*,  therapeutic use
Protein Binding
Pulmonary Artery / drug effects,  pathology
Rats, Sprague-Dawley
Vasodilator Agents / pharmacology*,  therapeutic use
Grant Support
Reg. No./Substance:
0/Peptide Fragments; 0/Phosphodiesterase 5 Inhibitors; 0/Vasodilator Agents; 10102-43-9/Nitric Oxide; 7665-99-8/Cyclic GMP; EC Oxide Synthase Type III; EC Nucleotide Phosphodiesterases, Type 5

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