Document Detail


Cytoskeletal role in protection of the failing heart by β-adrenergic blockade.
MedLine Citation:
PMID:  22081703     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Formation of a dense microtubule network that impedes cardiac contraction and intracellular transport occurs in severe pressure overload hypertrophy. This process is highly dynamic, since microtubule depolymerization causes striking improvement in contractile function. A molecular etiology for this cytoskeletal alteration has been defined in terms of type 1 and type 2A phosphatase-dependent site-specific dephosphorylation of the predominant myocardial microtubule-associated protein (MAP)4, which then decorates and stabilizes microtubules. This persistent phosphatase activation is dependent upon ongoing upstream activity of p21-activated kinase-1, or Pak1. Because cardiac β-adrenergic activity is markedly and continuously increased in decompensated hypertrophy, and because β-adrenergic activation of cardiac Pak1 and phosphatases has been demonstrated, we asked here whether the highly maladaptive cardiac microtubule phenotype seen in pathological hypertrophy is based on β-adrenergic overdrive and thus could be reversed by β-adrenergic blockade. The data in this study, which were designed to answer this question, show that such is the case; that is, β(1)- (but not β(2)-) adrenergic input activates this pathway, which consists of Pak1 activation, increased phosphatase activity, MAP4 dephosphorylation, and thus the stabilization of a dense microtubule network. These data were gathered in a feline model of severe right ventricular (RV) pressure overload hypertrophy in response to tight pulmonary artery banding (PAB) in which a stable, twofold increase in RV mass is reached by 2 wk after pressure overloading. After 2 wk of hypertrophy induction, these PAB cats during the following 2 wk either had no further treatment or had β-adrenergic blockade. The pathological microtubule phenotype and the severe RV cellular contractile dysfunction otherwise seen in this model of RV hypertrophy (PAB No Treatment) was reversed in the treated (PAB β-Blockade) cats. Thus these data provide both a specific etiology and a specific remedy for the abnormal microtubule network found in some forms of pathological cardiac hypertrophy.
Authors:
Guangmao Cheng; Harinath Kasiganesan; Catalin F Baicu; J Grace Wallenborn; Dhandapani Kuppuswamy; George Cooper
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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:  2011-11-11
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  302     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-02-01     Completed Date:  2012-03-20     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H675-87     Citation Subset:  IM    
Affiliation:
Gazes Cardiac Research Institute, PO Box 250773, Medical Univ. of South Carolina, 114 Doughty St., Charleston, SC 29403, USA.
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MeSH Terms
Descriptor/Qualifier:
Adrenergic beta-1 Receptor Antagonists / pharmacology*
Adrenergic beta-2 Receptor Antagonists / pharmacology*
Adrenergic beta-Agonists / pharmacology
Animals
Cardiomegaly / drug therapy,  metabolism,  physiopathology
Cats
Disease Models, Animal
Female
Heart Failure / drug therapy*,  metabolism,  physiopathology*
Isoproterenol / pharmacology
Male
Microtubule-Associated Proteins / metabolism
Microtubules / metabolism*
Myocytes, Cardiac / drug effects,  physiology
Propranolol / pharmacology*
Protein Phosphatase 1 / metabolism
Protein Phosphatase 2 / metabolism
Sarcomeres / enzymology,  physiology
Tubulin / metabolism
p21-Activated Kinases / metabolism
Grant Support
ID/Acronym/Agency:
HL-094545/HL/NHLBI NIH HHS; HL-104287/HL/NHLBI NIH HHS; RHL-092124//PHS HHS
Chemical
Reg. No./Substance:
0/Adrenergic beta-1 Receptor Antagonists; 0/Adrenergic beta-2 Receptor Antagonists; 0/Adrenergic beta-Agonists; 0/MAP4; 0/Microtubule-Associated Proteins; 0/Tubulin; 525-66-6/Propranolol; 7683-59-2/Isoproterenol; EC 2.7.11.1/p21-Activated Kinases; EC 3.1.3.16/Protein Phosphatase 1; EC 3.1.3.16/Protein Phosphatase 2
Comments/Corrections

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