Document Detail

Exogenous ubiquitin modulates chronic β-adrenergic receptor-stimulated myocardial remodeling: role in Akt activity and matrix metalloproteinase expression.
MedLine Citation:
PMID:  23042947     Owner:  NLM     Status:  MEDLINE    
β-Adrenergic receptor (β-AR) stimulation increases extracellular ubiquitin (UB) levels, and extracellular UB inhibits β-AR-stimulated apoptosis in adult cardiac myocytes. This study investigates the role of exogenous UB in chronic β-AR-stimulated myocardial remodeling. l-Isoproterenol (ISO; 400 μg·kg(-1)·h(-1)) was infused in mice in the presence or absence of UB (1 μg·g(-1)·h(-1)). Left ventricular (LV) structural and functional remodeling was studied 7 days after infusion. UB infusion enhanced serum UB levels. In most parts, UB alone had no effect on morphometric or functional parameters. Heart weight-to-body weight ratios were increased to a similar extent in the ISO and UB + ISO groups. Echocardiographic analyses showed increased percent fractional shortening, ejection fraction, and LV circumferential stress and fiber-shortening velocity in the ISO group. These parameters were significantly lower in UB + ISO vs. ISO. Isovolumic contraction and relaxation times and ejection time were significantly lower in ISO vs. UB + ISO. The increase in the number of TUNEL-positive myocytes and fibrosis was significantly higher in ISO vs. UB + ISO. Activation of Akt was higher, whereas activation of GSK-3β and JNKs was lower in UB + ISO vs ISO. Expression of MMP-2, MMP-9, and TIMP-2 was higher in UB + ISO vs ISO. In isolated cardiac fibroblasts, UB enhanced expression of MMP-2 and TIMP-2 in the presence of ISO. Neutralizing UB antibodies negated the effects of UB on MMP-2 expression, whereas recombinant UB enhanced MMP-2 expression. UB activated Akt, and inhibition of Akt inhibited UB + ISO-mediated increases in MMP-2 expression. Thus, exogenous UB plays an important role in β-AR-stimulated myocardial remodeling with effects on LV function, fibrosis, and myocyte apoptosis.
Christopher R Daniels; Cerrone R Foster; Sana Yakoob; Suman Dalal; William L Joyner; Mahipal Singh; Krishna Singh
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-10-05
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  303     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-17     Completed Date:  2013-04-09     Revised Date:  2013-12-18    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1459-68     Citation Subset:  IM    
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MeSH Terms
Apoptosis / drug effects
Disease Models, Animal
Glycogen Synthase Kinase 3 / metabolism
MAP Kinase Kinase 4 / metabolism
Matrix Metalloproteinase 2 / metabolism*
Matrix Metalloproteinase 9 / metabolism*
Mice, Inbred ICR
Myocardium / pathology
Myocytes, Cardiac / pathology
Proto-Oncogene Proteins c-akt / physiology*
Receptors, Adrenergic, beta / drug effects*,  physiology*
Tissue Inhibitor of Metalloproteinase-2 / metabolism
Ubiquitin / pharmacology*
Ventricular Dysfunction, Left / physiopathology
Ventricular Remodeling / drug effects*,  physiology*
Grant Support
Reg. No./Substance:
0/Receptors, Adrenergic, beta; 0/Ubiquitin; 127497-59-0/Tissue Inhibitor of Metalloproteinase-2; EC Proteins c-akt; EC synthase kinase 3 beta; EC Synthase Kinase 3; EC Kinase Kinase 4; EC Metalloproteinase 2; EC Metalloproteinase 9

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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