| 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 |
Related Documents
:
|
20605853 - Augmentation pressure and subendocardial viability ratio are associated with microalbum... 19332353 - Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre ... 21178123 - Glycerol-induced fluid shifts attenuate the vestibulosympathetic reflex in humans. |
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: 2013-04-08 |
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. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| 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 | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Testosterone-induced relaxation of coronary arteries: activation of BKCa channels via the cGMP-depen...
Next Document: Aldosterone-induced brain MAPK signaling and sympathetic excitation are angiotensin II type-1 recept...