Role of microtubules in contractile dysfunction of hypertrophied cardiocytes.

Abstract

Cardiac hypertrophy in response to systolic pressure overloading frequently results in contractile dysfunction, the cause for which has been unknown. Since, in contrast, the same degree and duration of hypertrophy in response to systolic volume overloading does not result in contractile dysfunction, we postulated that the contractile dysfunction of pressure hypertrophied myocardium might result from a direct effect of stress as opposed to strain loading on an intracellular structure of the hypertrophied cardiocyte. The specific hypothesis tested here is that the microtubule component of the cytoskeleton is such an intracellular structure, which, forming in excess, impedes sarcomere motion. The feline right ventricle was either pressure overloaded by pulmonary artery banding or volume overloaded by atrial septotomy. The quantity of microtubules was estimated from immunoblots and immunofluorescent micrographs, and their mechanical effects were assessed by measuring sarcomere motion during microtubule depolymerization. We show here that stress loading increases the microtubule component of the cardiac muscle cell cytoskeleton; this apparently is responsible for the entirety of the cellular contractile dysfunction seen in our model of pressure-hypertrophied myocardium. No such effects were seen in right ventricular cardiocytes from normal or volume-overloaded cats or in left ventricular cardiocytes from any group of cats. Importantly, the linked microtubule and contractile abnormalities are persistent and thus may be found to have significance for the deterioration of initially compensatory cardiac hypertrophy into the congestive heart failure state.

Mechanisms associated with the negative inotropic effect of deuterium oxide in single rat ventricular myocytes

“…In another series of experiments (not shown for brevity), 50% DµO had very similar qualitative and quantitative effects on isometric contractions of isolated ferret papillary muscles at 30°C, suggesting that our observations were not uniquely dependent upon of our experimental conditions. Single myocytes were exposed to colchicine (245 ìÒ for at least 30 min) in order to test for a possible role for microtubules (Tsutsui et al 1993(Tsutsui et al , 1994Ishibashi, et al 1996;Howarth et al 1999;Cicogna, et al 1999) in the negative inotropic effect of DµO. This agent has been reported to disrupt microtubles following a 1 h exposure at 10 ìÒ and to reverse microtubule-induced negative inotropic effects (Tsutsui et al 1993(Tsutsui et al , 1994Ishibashi et al 1996).…”

“…Single myocytes were exposed to colchicine (245 ìÒ for at least 30 min) in order to test for a possible role for microtubules (Tsutsui et al 1993(Tsutsui et al , 1994Ishibashi, et al 1996;Howarth et al 1999;Cicogna, et al 1999) in the negative inotropic effect of DµO. This agent has been reported to disrupt microtubles following a 1 h exposure at 10 ìÒ and to reverse microtubule-induced negative inotropic effects (Tsutsui et al 1993(Tsutsui et al , 1994Ishibashi et al 1996). Prior incubation with colchicine had no significant effects on either the amplitude or time course of contraction of single rat myocytes (in agreement with previous findings on control animals from Tsutsui et al 1993Tsutsui et al , 1994Ishibashi et al 1996;Cicogna, et al 1999).…”

“…This agent has been reported to disrupt microtubles following a 1 h exposure at 10 ìÒ and to reverse microtubule-induced negative inotropic effects (Tsutsui et al 1993(Tsutsui et al , 1994Ishibashi et al 1996). Prior incubation with colchicine had no significant effects on either the amplitude or time course of contraction of single rat myocytes (in agreement with previous findings on control animals from Tsutsui et al 1993Tsutsui et al , 1994Ishibashi et al 1996;Cicogna, et al 1999). Upon exposure to 50% DµO, in the continued presence of colchicine, cell shortening was reduced from 7.4 ± 1.1 to 2.7 ± 0.5% of resting cell length (n = 13, P < 0.05; Fig.…”

“…Proliferation of microtubules during hypertrophy (e.g. Tsutsui et al 1993Tsutsui et al , 1994 or by use of agents such as Taxol (Tsutsui et al 1994;Howarth et al 1999) have been shown to reduce myocyte contraction. DµO is used to modulate microtubules in cardiac muscle (e.g.…”

“…DµO is used to modulate microtubules in cardiac muscle (e.g. Takahashi et al 1998) and it has been suggested that acute proliferation of microtubules by DµO can explain its reduction of the contraction of cardiac myocytes (Tsutsui et al 1993(Tsutsui et al , 1994. If DµO were to rapidly polymerize microtubules, in the absence of other effects, in cardiac muscle, it would not only explain the contractile effects of DµO but, perhaps more importantly, it would identify DµO as the agent of choice for microtubule proliferation, as agents such as Taxol require several hours for their effects on microtubules to develop (Tsutsui et al 1994;Howarth et al 1999).…”