Document Detail


N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth-regulatory lectin.
MedLine Citation:
PMID:  19098114     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Galectin-3 (Gal-3) is secreted by activated macrophages. In hypertension, Gal-3 is a marker for hypertrophic hearts prone to develop heart failure. Gal-3 infused in pericardial sac leads to cardiac inflammation, remodeling, and dysfunction. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a naturally occurring tetrapeptide, prevents and reverses inflammation and collagen deposition in the heart in hypertension and heart failure postmyocardial infarction. In the present study, we hypothesize that Ac-SDKP prevents Gal-3-induced cardiac inflammation, remodeling, and dysfunction, and these effects are mediated by the transforming growth factor (TGF)-beta/Smad3 signaling pathway. Adult male rats were divided into four groups and received the following intrapericardial infusion for 4 wk: 1) vehicle (saline, n = 8); 2) Ac-SDKP (800 microg x kg(-1) x day(-1), n = 8); 3) Gal-3 (12 microg/day, n = 7); and 4) Ac-SDKP + Gal-3 (n = 7). Left ventricular ejection fraction, cardiac output, and transmitral velocity were measured by echocardiography; inflammatory cell infiltration, cardiomyocyte hypertrophy, and collagen deposition in the heart by histological and immunohistochemical staining; and TGF-beta expression and Smad3 phosphorylation by Western blot. We found that, in the left ventricle, Gal-3 1) enhanced macrophage and mast cell infiltration, increased cardiac interstitial and perivascular fibrosis, and causes cardiac hypertrophy; 2) increased TGF-beta expression and Smad3 phosphorylation; and 3) decreased negative change in pressure over time response to isoproterenol challenge, ratio of early left ventricular filling phase to atrial contraction phase, and left ventricular ejection fraction. Ac-SDKP partially or completely prevented these effects. We conclude that Ac-SDKP prevents Gal-3-induced cardiac inflammation, fibrosis, hypertrophy, and dysfunction, possibly via inhibition of the TGF-beta/Smad3 signaling pathway.
Authors:
Yun-He Liu; Martin D'Ambrosio; Tang-dong Liao; Hongmei Peng; Nour-Eddine Rhaleb; Umesh Sharma; Sabine André; Hans-J Gabius; Oscar A Carretero
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-12-19
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  296     ISSN:  0363-6135     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2009 Feb 
Date Detail:
Created Date:  2009-01-27     Completed Date:  2009-03-12     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H404-12     Citation Subset:  IM    
Affiliation:
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Inflammatory Agents / administration & dosage,  blood,  pharmacology*
Blood Pressure / drug effects
Body Weight / drug effects
Cardiac Output / drug effects
Cardiomegaly / chemically induced,  metabolism,  physiopathology,  prevention & control*
Cardiotonic Agents / administration & dosage,  blood,  pharmacology*
Collagen / metabolism
Disease Models, Animal
Echocardiography, Doppler
Fibrosis
Galectin 3
Heart Rate / drug effects
Hemodynamics / drug effects*
Inflammation / chemically induced,  metabolism,  physiopathology,  prevention & control*
Infusions, Parenteral
Isoproterenol / pharmacology
Macrophages / drug effects,  pathology
Male
Mast Cells / drug effects,  pathology
Myocardial Contraction / drug effects
Myocardium / metabolism,  pathology
Oligopeptides / administration & dosage,  blood,  pharmacology*
Phosphorylation
Rats
Rats, Sprague-Dawley
Signal Transduction / drug effects
Smad3 Protein / metabolism
Stroke Volume / drug effects
Time Factors
Transforming Growth Factor beta / metabolism
Ventricular Function, Left / drug effects*
Ventricular Remodeling / drug effects*
Grant Support
ID/Acronym/Agency:
HL071806/HL/NHLBI NIH HHS; HL28982/HL/NHLBI NIH HHS; R01 HL071806/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents; 0/Cardiotonic Agents; 0/Galectin 3; 0/Madh3 protein, rat; 0/Oligopeptides; 0/Smad3 Protein; 0/Transforming Growth Factor beta; 7683-59-2/Isoproterenol; 9007-34-5/Collagen; H041538E9P/goralatide
Comments/Corrections

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