title: Cytoskeletal role in protection of the failing heart by β-adrenergic blockade.
abstract: 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.affiliation: Gazes Cardiac Research Institute, PO Box 250773, Medical Univ. of South Carolina, 114 Doughty St., Charleston, SC 29403, USA.
authors.forename: Guangmao
authors.initials: G
authors.lastname: Cheng
authors.forename: Harinath
authors.initials: H
authors.lastname: Kasiganesan
authors.forename: Catalin F
authors.initials: CF
authors.lastname: Baicu
authors.forename: J Grace
authors.initials: JG
authors.lastname: Wallenborn
authors.forename: Dhandapani
authors.initials: D
authors.lastname: Kuppuswamy
authors.forename: George
authors.initials: G
authors.lastname: Cooper
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology*; D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002415:Cats; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D011433:Propranolol / Q000494:pharmacology*; D054645:Protein Phosphatase 1 / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D012518:Sarcomeres / Q000201:enzymology / Q000502:physiology; D014404:Tubulin / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D008869:Microtubule-Associated Proteins; D014404:Tubulin; D011433:Propranolol; D054462:p21-Activated Kinases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D007545:Isoproterenol
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