Chronic doxorubicin cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway and attenuated by pitavastatin through the inhibition of Rac1 activity

Yoshida, Masashi; Shiojima, Ichiro; Ikeda, Hiroyuki; Komuro, Issei

doi:10.1016/j.yjmcc.2009.07.024

Cited by 162 publications

(139 citation statements)

References 25 publications

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“…HSP20, HSP21, HSP2, HSP70) can be either cardioprotective or detrimental in this setting (Liu et al, 2007; Vedam et al, 2010; Wang et al, 2016). Other putative mechanisms include damage to nuclear DNA, disruption of sarcomeric protein synthesis (Ito et al, 1990), accumulation of the tumour suppressor protein, p53 (Yoshida et al, 2009) and a disturbance of energy metabolism (Tokarska‐Schlattner et al, 2006). In mitochondria, increased ROS leads to Ca 2+ overload, which triggers mitochondrial permeability transition, resulting in loss of membrane potential, swelling and outer membrane rupture, and consequent activation of caspases, release of cytochrome c and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

McLaughlin

Zhao

O’Neill

et al. 2017

British J Pharmacology

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Background and PurposeThe anthracycline doxorubicin (DOX), although successful as a first‐line cancer treatment, induces cardiotoxicity linked with increased production of myocardial ROS, with Nox2 NADPH oxidase‐derived superoxide reported to play a key role. The aim of this study was to identify novel mechanisms underlying development of cardiac remodelling/dysfunction further to DOX‐stimulated Nox2 activation.Experimental ApproachNox2−/− and wild‐type (WT) littermate mice were administered DOX (12 mg·kg−1 over 3 weeks) prior to study at 4 weeks. Detailed mechanisms were investigated in murine HL‐1 cardiomyocytes, employing a robust model of oxidative stress, gene silencing and pharmacological tools.Key ResultsDOX‐induced cardiac dysfunction, cardiomyocyte remodelling, superoxide production and apoptosis in WT mice were attenuated in Nox2−/− mice. Transcriptional analysis of left ventricular tissue identified 152 differentially regulated genes (using adjusted P < 0.1) in DOX‐treated Nox2−/− versus WT mice, and network analysis highlighted ‘Cell death and survival’ as the biological function most significant to the dataset. The mitochondrial membrane protein, mitofusin‐2 (Mfn2), appeared as a strong candidate, with increased expression (1.5‐fold), confirmed by qPCR (1.3‐fold), matching clear published evidence of promotion of cardiomyocyte cell death. In HL‐1 cardiomyocytes, targeted siRNA knockdown of Nox2 decreased Mfn2 protein expression, but not vice versa. While inhibition of Nox2 activity along with DOX treatment attenuated its apoptotic and cytotoxic effects, reduced apoptosis after Mfn2 silencing reflected a sustained cytotoxic response and reduced cell viability.Conclusions and ImplicationsDOX‐induced and Nox2‐mediated up‐regulation of Mfn2, rather than contributing to cardiomyocyte dysfunction through apoptotic pathways, appears to promote a protective mechanism.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

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Section: Introductionmentioning

confidence: 99%

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

McLaughlin

Zhao

O’Neill

et al. 2017

British J Pharmacology

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“…29 Furthermore, intermittent hypoxia has been shown to induce an earlier and more extensive apoptotic response of rat pheochromocytoma PC-12 cells than sustained hypoxia. 30 Intriguingly, Yoshida et al 31 reported that pitavastatin was effective to suppress the oxidative DNA-damage-ATM-p53-apoptosis pathway through the inhibition of Rac1 activity. Although we have not confirmed apoptotic bodies in the LV myocardium, further studies focused on apoptosis induced by intermittent hypoxia should be addressed in the near future.…”

Section: Discussionmentioning

confidence: 99%

Pitavastatin reduces oxidative stress and attenuates intermittent hypoxia-induced left ventricular remodeling in lean mice

et al. 2010

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We have reported previously that intermittent hypoxia related to sleep apnea induces cardiovascular remodeling secondary to the oxidative stress. The aim of this study was to examine the effect of pitavastatin as an antioxidant to prevent intermittent hypoxia-induced left ventricular (LV) remodeling in mice without hypercholesterolemia. Eight-week-old male C57BL/6J mice (n¼35) were exposed to intermittent hypoxia (30 s exposure to 5% oxygen, followed by 30 s exposure to 21% oxygen) for 8 h per day during the daytime or maintained under normoxic conditions; in addition, they were either treated with pitavastatin (3 mg kg À1 per day) or vehicle for 10 days. After cardiac catheterization and blood sampling, the LV myocardium was examined. The systemic blood pressure and plasma level of total cholesterol were similar among the four groups. Intermittent hypoxia significantly increased the expression levels of 4-hydroxy-2-nonenal (4-HNE) proteins, TNF-a and TGF-b mRNA, and also the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling (TUNEL)-positive myocardial cells in the LV myocardium. In addition, enhanced hypertrophy of the cardiomyocytes, perivascular fibrosis and histological degeneration were observed in the mice exposed to hypoxic stress. Treatment with pitavastatin significantly suppressed the expression levels of the 4-HNE proteins, cytokines, superoxide production and TUNEL-positive myocardial cells in the LV myocardium, consequently attenuating the hypoxia-induced histological changes. Pitavastatin preserved, at least partially, the morphological structure of the LV myocardium in lean mice exposed to intermittent hypoxia, through its antioxidant effect.

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“…Recently, Sch B was found to stimulate cytochrome 450-catalyzed NADPH oxidation reaction resulting in low level of ROS production, which in turn triggers redox signaling through ERK/Nrf2 pathway so as to promote cell survival [28,29]. Yoshida et al suggested that pitavastatin attenuates chronic doxorubicin cardiotoxicity through its antioxidant effect involving Rac1 inhibition [30]. Since Rac1 is a requisite component of NADPH oxidase, its role in Sch B-induced antioxidant activity remains to be studied.…”

Section: Discussionmentioning

confidence: 99%

235 Schisandrin B prevents doxorubicin-induced chronic cardiotoxicity and enhances its anticancer activity in vivo

Hu¹,

Xu²,

Sun³

et al. 2010

European Journal of Cancer Supplements

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Chronic doxorubicin cardiotoxicity is mediated by oxidative DNA damage-ATM-p53-apoptosis pathway and attenuated by pitavastatin through the inhibition of Rac1 activity

Cited by 162 publications

References 25 publications

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

Pitavastatin reduces oxidative stress and attenuates intermittent hypoxia-induced left ventricular remodeling in lean mice

235 Schisandrin B prevents doxorubicin-induced chronic cardiotoxicity and enhances its anticancer activity in vivo

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