Abstract
Increased microtubule density, through viscous loading of active myofilaments, causes contractile dysfunction of hypertrophied and failing pressure-overloaded myocardium, which is normalized by microtubule depolymerization. We have found this to be based on augmented tubulin synthesis and microtubule stability. We show here that increased tubulin synthesis is accounted for by marked transcriptional up-regulation of the beta1- and beta2-tubulin isoforms, that hypertrophic regulation of these genes recapitulates their developmental regulation, and that the greater proportion of beta1-tubulin protein may have a causative role in the microtubule stabilization found in cardiac hypertrophy.
Highlights
Increased microtubule density, through viscous loading of active myofilaments, causes contractile dysfunction of hypertrophied and failing pressure-overloaded myocardium, which is normalized by microtubule depolymerization
We have found that this cardiocyte contractile defect is caused by increased density of the cellular microtubule network [3], which imposes a viscous load on the shortening sarcomeres during contraction [4]
In attempting to uncover the cause of increased microtubule density in hypertrophied cardiocytes, we focused on increased tubulin synthesis [5] and microtubule formation as well as on increased stability of the microtubules once formed
Summary
Through viscous loading of active myofilaments, causes contractile dysfunction of hypertrophied and failing pressure-overloaded myocardium, which is normalized by microtubule depolymerization. The left panels show an immunoblot analysis of -tubulin isoforms in soluble cytosolic and cold-stable cytoskeletal fractions of the RV and LV of a cat heart 2 weeks after RV pressure overloading.
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