Doxorubicin cardiomyopathy is associated with a decrease in calcium release channel of the sarcoplasmic reticulum in a chronic rabbit model.

Abstract

Doxorubicin is a highly effective cancer chemotherapeutic agent that produces a dose-dependent cardiomyopathy that limits its clinical usefulness. Clinical and animal studies ofmorphological changes during the early stages of doxorubicin-induced cardiomyopathy have suggested that the sarcoplasmic reticulum, the intracellular membrane system responsible for myoplasmic calcium regulation in adult mammalian heart, may be the early target of doxorubicin. To detect changes in the calcium pump protein or the calcium release channel (ryanodine receptor) of the sarcoplasmic reticulum during chronic doxorubicin treatment, rabbits were treated with intravenous doxorubicin (1 mg/kg) twice weekly for 12 to 18 doses. Pair-fed controls received intravenous normal saline. The severity ofcardiomyopathy was scored by light and electron microscopy of left ventricular papillary muscles. Developed tension was measured in isolated atrial strips. In subcellular fractions from heart, I3Hjryanodine binding was decreased in doxorubicin-treated rabbits (0.33±0.03 pmol/mg) compared with control rabbits (0.66±0.02 pmol/mg, P < 0.0001). The magnitude of the decrease in I3Hjryanodine binding correlated with both the severity of the cardiomyopathy graded by pathology score (light and electron microscopy) and the decrease in developed tension in isolated atrial strips. B. for [3Hlryanodine binding and the amount of immunoreactive ryanodine receptor by Western blot analysis using sequence-specific antibody were both decreased, consistent with a decrease in the amount of calcium release channel of sarcoplasmic reticulum in doxorubicin-treated rabbits. In contrast, there was no decrease in the amount or the activity of the calcium pump protein of the sarcoplasmic reticulum in doxorubicin-treated rabbits. Doxorubicin treatment did not decrease [3H I ryanodine binding or the amount ofimmunoreactive calcium release channel of sarcoplasmic reticulum in skeletal muscle. Since the sarcoplasmic reticulum regulates muscle contraction by the cyclic uptake and release of a large internal calcium pool, altered function of the calcium release channel could lead to the abnormalities ofcontraction and relaxation observed in the doxorubicin cardiomyopathy. (J. Clin.A portion of this paper has been presented in abstract form ( 1991.Biophys. J. 59: lOla).

Neuregulin1-ErbB Signaling in Doxorubicin-Induced Cardiotoxicity

“…These results are consistent with the findings in doxorubicin-treated patients (Brown et al, 1989b;Barry et al, 2007a). Doxorubicin-induced reduction of cardiomyocyte contractility is often associated with decreased expression of SERCA2a (Dodd et al, 1993;Boucek et al, 1999;Gambliel et al, 2002), suggesting that impaired SERCA2a function may contribute to doxorubicin-induced cardiomyocyte contractile dysfunction.…”

“…In the early stage of the disease, doxorubicin tends to induce Ca 2+ release from SR and increase cardiomyocyte contractility (Brown et al, 1989b;Kim et al, 1989;Ondrias et al, 1990;Kapelko et al, 1996). In the late stage of the disease, doxorubicin inhibits Ca 2+ regulatory proteins and reduces cardiomyocyte contractility (Ondrias et al, 1990;Dodd et al, 1993;Maeda et al, 1998;Boucek et al, 1999;Chugun et al, 2000;Gambliel et al, 2002;Timolati et al, 2006). In a subacute doxorubicin mouse model, doxorubicin induces an increase in cardiac contractile function as measured by dP/dtmax and dP/dtmin during the first few days after the doxorubicin injection; however, cardiac function declines later on (our unpublished data).…”

Kinetic isoforms of intramembrane charge in intact amphibian striated muscle.

“…Ryanodine (0.1-500 I~M) specifically inactivates Ca 2+ release in isolated rabbit junctional SR membranes, given optimum equilibrium conditions for receptor binding (Zimanyi et al, 1992;Rouseau et al, 1987;Meissner, 1994). Aalthraquinones such as daunorubicin are cardiotoxic cancer chemotherapeutic agents (Dodd et al, 1993) that act on sarcoplasmic reticular Ca 2+ release channels in lipid bilayers (Holmberg and Williams, 1990) and specifically influence ryanodine binding to sarcoplasmic reticular membranes and soluble receptor preparations (Pessah et al, 1990;Bowling et al, 1994). They alter Ca 2+ movements and tension generation in guineapig cardiac muscle at concentrations (100-200 I~M) similar to those used here (Hagane et al, 1988).…”

Doxorubicin-Indused Disturbances of Cardiomyocyte Contractile Activity

“…Також з огляду на спорід-неність доксорубіцину з кардіоліпіном та властивістю мітохондрій депонувати велику кількість Са 2+ , можна припустити, що на дію цього препарату органели клітини відпові-дають підвищеним накопиченням Са 2+ . При цьому, виявлено, що метаболічна активність та сарколемальна Са 2+ -АТФаза (SERCA) пригнічується [10]. Всі ці порушення можуть призводити до захворювань серцево-судинної системи і тому пошук механізмів можливої кардіопротекції є надзвичайно актуальним.…”