A direct test of the hypothesis that increased microtubule network density contributes to contractile dysfunction of the hypertrophied heart.
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 beta(4)-tubulin with beta(1)-tubulin mutants that had been selected for their effects on microtubule stability and thus microtubule network density. In each case, the replacement of cardiac beta(4)-tubulin with mutant hemagglutinin-tagged beta(1)-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.
Cheng
Guangmao
G
Cardiology Division, Gazes Cardiac Research Institute, Medical University of South Carolina, 114 Doughty Street, Charleston, SC 29403, USA.
Zile
Michael R
MR
Takahashi
Masaru
M
Baicu
Catalin F
CF
Bonnema
D Dirk
DD
Cabral
Fernando
F
Menick
Donald R
DR
Cooper
George
G
D000818:Animals; D006224:Cricetinae; D004195:Disease Models, Animal; D005838:Genotype; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D010641:Phenotype; D014404:Tubulin / Q000235:genetics / Q000378:metabolism*; D016277:Ventricular Function, Left
D014404:Tubulin