BASIS FOR INCREASED MICROTUBULES IN PRESSURE-HYPERTROPHIED CARDIOCYTES

Background We have shown on the levels of the sarcomere and the cardio cyte that a persistent increase in microtubule density accounts to a r emarkable degree for the contractile dysfunction seen in pressure-over load right ventricular hypertrophy. In the present study, we have aske d whether these linked phenotypic and contractile abnormalities are an immediate and direct effect of load input into the cardiocyte or inst ead a concomitant of hypertrophic growth in response to pressure overl oading. Methods and Results The feline right ventricle was pressure-ov erloaded by pulmonary artery banding. The quantity of microtubules was estimated from immunoblots and immunofluorescent micrographs, and the ir mechanical effects were assessed by measuring sarcomere motion duri ng microtubule depolymerization. The biogenesis of microtubules was es timated from Northern and Western blot analyses of tubulin mRNAs and p roteins. These measurements were made in control cats and in operated cats during and after the completion of right ventricular hypertrophy; the left ventricle from each heart served as a normally loaded same-a nimal control. We have shown that the alterations in microtubule densi ty and sarcomere mechanics are not an immediate consequence of pressur e overloading but instead appear in parallel with the load-induced inc rease in cardiac mass. Of potential mechanistic importance, both these changes and increases in tubulin poly A(+) mRNA and protein coexist i ndefinitely after a new, higher steady state of right ventricular mass is reached. Conclusions Because we find persistent increases both in microtubules and in their biosynthetic precursors in pressure-hypertro phied myocardium, the mechanisms for this cytoskeletal abnormality mus t be sought through studies of the control both of microtubule stabili ty and of tubulin synthesis.