Phenotypic consequences of beta1-tubulin expression and MAP4 decoration of microtubules in adult cardiocytes.
In pressure-overload cardiac hypertrophy, microtubule network densification is one cause of contractile dysfunction. Cardiac transcriptional upregulation of beta1-tubulin rather than the constitutive beta4-tubulin and of microtubule-associated protein (MAP)4 accompanies hypertrophy, with extensive microtubule decoration by MAP4. Because MAP4 stabilizes microtubules, and because the isoform-variable carboxy terminus of beta-tubulin binds to MAP4, we wished to determine whether one or both of these proteins has etiologic significance for cardiac microtubule network densification. Recombinant adenoviruses encoding beta1-tubulin, beta4-tubulin, and MAP4 were used to infect isolated cardiocytes. Overexpressed MAP4 caused a shift of tubulin dimers to the polymerized fraction and formation of a dense, stable microtubule network. Overexpressed beta1- or beta4-tubulin had neither any independent effect on these variables nor any effect additive to that of simultaneously overexpressed MAP4. Results from transgenic mice with cardiac overexpression of beta1-tubulin or MAP4 were confirmatory, but unlike the effects of brief adenovirus-mediated MAP4 overexpression in isolated cardiocytes, MAP4 transgenic hearts showed a marked increase in total alpha- and beta-tubulin. Thus MAP4 overexpression caused increased tubulin expression, formation of stable microtubules, and altered microtubule network properties, such that MAP4 upregulation may be one cause for the dense, stable microtubule network characteristic of pressure-overloaded, hypertrophied cardiocytes.
Takahashi
Masaru
M
Gazes Cardiac Research Institute, PO Box 250773, Medical University of South Carolina, 114 Doughty Street, Charleston, SC 29403, USA.
Shiraishi
Hirokazu
H
Ishibashi
Yuji
Y
Blade
Kristie L
KL
McDermott
Paul J
PJ
Menick
Donald R
DR
Kuppuswamy
Dhandapani
D
Cooper
George
G
D000256:Adenoviridae / Q000235:genetics; D000367:Age Factors; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000503:physiopathology; D002415:Cats; D002478:Cells, Cultured; D006224:Cricetinae; D018014:Gene Transfer Techniques; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic; D014404:Tubulin / Q000235:genetics* / Q000378:metabolism
D008869:Microtubule-Associated Proteins; D014404:Tubulin; D018995:Myosin Heavy Chains