Fas-Mediated Apoptosis in Adriamycin-Induced Cardiomyopathy in Rats

Nakamura, Tsuneyuki; Ueda, Yoshimichi; Yang, Juan; Katsuda, Shogo; Takahashi, Hiroaki; Koh, Eikan

doi:10.1161/01.cir.102.5.572

Cited by 200 publications

(140 citation statements)

References 31 publications

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“…Altogether, this indicates the involvement of caspase-independent apoptotic routes in mediating death in cardiac myocytes by DOX. This cannot be generalised because in other cell types (in our study and in previous reports) caspases seem to play a role in DOX-induced cell death (Nakamura et al, 2000;Grassilli et al, 2004;Kalivendi et al, 2005). Together this supports the idea that more than one mechanism can mediate programmed cell death, which depends on both the death stimulus provided and the cell type studied (Bröker et al, 2005).…”

Section: Discussionsupporting

confidence: 63%

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

et al. 2007

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Doxorubicin (DOX) is an antitumour agent for different types of cancer, but the dose-related cardiotoxicity limits its clinical use. To prevent this side effect we have developed the flavonoid monohydroxyethylrutoside (monoHER), a promising protective agent, which did not interfere with the antitumour activity of DOX. To obtain more insight in the mechanism underlying the selective protective effects of monoHER, we investigated whether monoHER (1 mM) affects DOX-induced apoptosis in neonatal rat cardiac myocytes (NeRCaMs), human endothelial cells (HUVECs) and the ovarian cancer cell lines A2780 and OVCAR-3. DOX-induced cell death was effectively reduced by monoHER in heart, endothelial and A2780 cells. OVCAR-3 cells were highly resistant to DOXinduced apoptosis. Experiments with the caspase-inhibitor zVAD-fmk showed that DOX-induced apoptosis was caspase-dependent in HUVECs and A2780 cells, whereas caspase-independent mechanisms seem to be important in NeRCaMs. MonoHER suppressed DOX-dependent activation of the mitochondrial apoptotic pathway in normal and A2780 cells as illustrated by p53 accumulation and activation of caspase-9 and -3 cleavage. Thus, monoHER acts by suppressing the activation of molecular mechanisms that mediate either caspase-dependent or -independent cell death. In light of the current work and our previous studies, the use of clinically achievable concentrations of monoHER has no influence on the antitumour activity of DOX whereas higher concentrations as used in the present study could influence the antitumour activity of DOX.

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Section: Discussionsupporting

confidence: 63%

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

et al. 2007

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“…ADR caused decreased blood pressure (MBP, SBP, and DBP); this was probably responsible for the decreased LV function due to a decreasd ratio of LV to body weight. The decline of LV weight may be explained by myofibrillar loss associated with inducion of apoptosis and due to the inhibition of the expression of some genes specific for cardiac muscles, such as a-actin, troponin by ADR (Boucek et al 1999;Nakamura et al 2000). The compensation mechanism e.g.…”

Section: Discussionmentioning

confidence: 99%

Acute adriamycin-induced cardiotoxicity is exacerbated by angiotension II

et al. 2014

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Adriamycin (ADR) increases the production of reactive oxygen species (ROS), which diminishes mitochondrial function. Angiotensin-II stimulates mitochondrial ROS generation. The aim of the study was to examine whether angiotensin converting enzyme (ACE) or renin inhibitors protect against ADR-induced mitochondrial function impairment. Rats were divided into five groups as control, ADR, co-treatment ADR with captopril, co-treatment ADR with aliskiren, co-treatment ADR with both captopril and aliskiren. Left ventricular function and blood pressures were assessed at the end of treatment period. Mitochondrial membrane potential (MMP) and ATP levels were determined. ADR treatment decreased the left ventricular pressure and increased the left ventricular end-diastolic pressure. ADR decreased MMP and ATP levels in myocyte mitochondria due to increasing oxidative stress. ADR decreased MMP and ATP levels due to increased oxidative stress in the heart. Inhibitors of ACE and renin caused the elevation of the decreased of MMP and ATP levels. The pathologic changes in electrocardiogram, blood pressure and left ventricular function were decreased by inhibition of Ang-II production. We concluded that inhibitors of angiotensin II are effective against ADR cardiotoxicity via the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo.

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“…It has been reported that numerous signaling molecules, such as cytochrome c, Bcl-2, Bax, p53, and Fas, have been implicated in the apoptotic pathways of cardiomyocytes [15,16] . Bcl-2 family members include Bax, Bcl-2, and Bcl-xl.…”

Section: Discussionmentioning

confidence: 99%

Liguzinediol improved the heart function and inhibited myocardial cell apoptosis in rats with heart failure

Song

Zhu

et al. 2014

Acta Pharmacol Sin

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Aim: Liguzinediol is a novel derivative of ligustrazine isolated from the traditional Chinese medicine Chuanxiong (Ligusticum wallichii Franch), and produces significant positive inotropic effect in isolated rat hearts. In this study we investigated the effects of liguzinediol on a rat model of heart failure. Methods: To induce heart failure, male SD rats were injected with doxorubicin (DOX, 2 mg/kg, ip) once a week for 4 weeks. Then the rats were administered with liguzinediol (5, 10, and 20 mg·kg -1 ·d -1 , po) for 2 weeks. Hemodynamic examination was conducted to evaluate heart function. Myocardial cell apoptosis was examined morphologically. The expression of related genes and proteins were analyzed using immunohistochemical staining and Western blot assays, respectively. Results: Oral administration of liguzinediol dose-dependently improved the heart function in DOX-treated rats. Electron microscopy revealed that liguzinediol (10 mg·kg -1 ·d -1 ) markedly attenuated DOX-induced injury of cardiomyocytes, and decreased the number of apoptotic bodies in cardiomyocytes. Furthermore, liguzinediol significantly decreased Bax protein level, and increased Bcl-2 protein level in cardiomyocytes of DOX-treated rats, led to an increase in the ratio of Bcl-2/Bax. Moreover, liguzinediol significantly decreased the expression of both cleaved caspase-3 and NF-κB in cardiomyocytes of DOX-treated rats. Administration of digitalis (0.0225 mg·kg -1 ·d -1 ) also markedly improved the heart function and the morphology of cardiomyocytes in DOX-treated rats. Conclusion: Liguzinediol improves the heart function and inhibits myocardial cell apoptosis in the rat model of heart failure, which is associated with regulating Bcl-2, Bax, caspase-3, and NF-κB expression.

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Fas-Mediated Apoptosis in Adriamycin-Induced Cardiomyopathy in Rats

Cited by 200 publications

References 31 publications

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

Acute adriamycin-induced cardiotoxicity is exacerbated by angiotension II

Liguzinediol improved the heart function and inhibited myocardial cell apoptosis in rats with heart failure

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