The initial goals of this project were to determine whether cytoskeletal alterations have a role in the contractile dysfunction of hypertrophied myocardium, and if so, what is their nature, their locus, and their cause. Important accomplishments have been 1) the demonstration of microtubule- based contractile dysfunction in cardiocytes from the hypertrophied and failing RV and LV, 2) extension of these findings to isolated tissue and to the intact heart, 3) biophysical characterization of the etiology of the microtubule-based contractile dysfunction, 4) the finding that this pathophysiological mechanism is tightly restricted to pressure overload- induced hypertrophy in which wall stress is increased, 5) the demonstration that microtubules are the only major extra-myofilament cytoskeletal protein so affected, 6) the finding that this phenomenon is based both on increased tubulin, and thus microtubules, and on increased stability of the microtubules once formed, 7) the finding that the major cardiac microtubule-stabilizing protein is markedly up-regulated in pressure overload cardiac hypertrophy, 8) the finding that transcriptional upregulation of two minor beta-tubulin isoforms during hypertrophy, which we found to mimic the developmental regulation of these genes, accounts for the increase in beta-tubulin, and 9) the demonstration that one of these isoforms may act synergistically with MAP 4 to stabilize microtubules in pressure overload cardiac hypertrophy. The first goal of the work proposed is to reduce the correlative relationship between microtubule network densification and cardiac contractile dysfunction to a cause-and-effect relationship via direct genetic manipulation of microtubule stability and via an exploration of the role of altered expression of genes encoding microtubule and microtubule-associated proteins found to date. The second goal is to extend this investigation from microtubule effects on cardiocyte constitutive properties to a consideration of more specific microtubule-dependent effects on cardiocyte constitutive properties to a consideration of more specific microtubule- dependent effects on the hypertrophied cell, and explicitly, a consideration of any role of increased density of the cardiocyte microtubule network in the beta-adrenergic receptor desensitization characteristic of cardiac hypertrophy.
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