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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/H2231    most recent ajpheart.91515.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Cheng, G. Articles by Cooper, G. PubMed PubMed Citation Articles by Cheng, G. Articles by Cooper, G., 4th

A direct test of the hypothesis that increased microtubule network density contributes to contractile dysfunction of the hypertrophied heart

¹Cardiology Division, Gazes Cardiac Research Institute, Medical University of South Carolina, and the Department of Veterans Affairs Medical Center, Charleston, South Carolina; and ²Department of Integrative Biology and Pharmacology, University of Texas Medical School, Houston, Texas

Submitted 21 December 2007 ; accepted in final form 11 March 2008

Contractile dysfunction in pressure overload-hypertrophied myocardium has been attributed in part to the increased density of a stabilized cardiocyte microtubule network. The present study, the first to employ wild-type and mutant tubulin transgenes in a living animal, directly addresses this microtubule hypothesis by defining the contractile mechanics of the normal and hypertrophied left ventricle (LV) and its constituent cardiocytes from transgenic mice having cardiac-restricted replacement of native β₄-tubulin with β₁-tubulin mutants that had been selected for their effects on microtubule stability and thus microtubule network density. In each case, the replacement of cardiac β₄-tubulin with mutant hemagglutinin-tagged β₁-tubulin was well tolerated in vivo. When LVs in intact mice and cardiocytes from these same LVs were examined in terms of contractile mechanics, baseline function was reduced in mice with genetically hyperstabilized microtubules, and hypertrophy-related contractile dysfunction was exacerbated. However, in mice with genetically hypostabilized cardiac microtubules, hypertrophy-related contractile dysfunction was ameliorated. Thus, in direct support of the microtubule hypothesis, we show here that cardiocyte microtubule network density, as an isolated variable, is inversely related to contractile function in vivo and in vitro, and microtubule instability rescues most of the contractile dysfunction seen in pressure overload-hypertrophied myocardium.

molecular biology; hypertrophy; heart failure