Manipulation of Cardiac Phosphatidylinositol 3-Kinase (PI3K)/Akt Signaling by Apoptosis Regulator through Modulating IAP Expression (ARIA) Regulates Cardiomyocyte Death during Doxorubicin-induced Cardiomyopathy

Kitamura, Yoshihisa; Koide, Masaaki; Akakabe, Yoshiki; Matsuo, Kiyonari; Shimoda, Yoshiaki; Soma, Yuka; Ogata, Toru; Ueyama, Tomomi; Matoba, Satoaki; Yamada, Hiroyuki; Ikeda, Koji

doi:10.1074/jbc.m113.508143

Cited by 47 publications

(45 citation statements)

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“…In particular, enhancement of MMP2 in cardiomyocytes in response to DOX has been identified as redox‐dependent (Spallarossa et al, 2006; Mukhopadhyay et al, 2009; Bartekova et al, 2015). Other significant changes induced by DOX and mediated by Nox2 indicated up‐regulation of gene expression and included increased phosphoinositide‐dependent protein kinase‐1, which is an important mediator of PI3K signalling, promoting cardiomyocyte survival via the PI3K‐Akt pathway (An et al, 2013; Kitamura et al, 2014). Similarly, DOX‐induced up‐regulation of HSP binding protein 1, which is implicated in maintaining redox homeostasis by upholding glutathione levels (Christians et al, 2012), may signify an attempt to promote survival by counteracting increased ROS production.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…Medial wall thickness was also determined as previously described (18). Wheat germ agglutinin (WGA) staining was performed as previously described (13).…”

Section: Mice and Hypoxia Experiments In Vivomentioning

confidence: 99%

Pyk2 aggravates hypoxia-induced pulmonary hypertension by activating HIF-1α

Fukai

Nakamura

Hoshino

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Pulmonary arterial hypertension (PAH) is a refractory disease characterized by uncontrolled vascular remodeling and elevated pulmonary arterial pressure. Although synthetic inhibitors of some tyrosine kinases have been used to treat PAH, their therapeutic efficacies and safeties remain controversial. Thus, the establishment of novel therapeutic targets based on the molecular pathogenesis underlying PAH is a clinically urgent issue. In the present study, we demonstrated that proline-rich tyrosine kinase 2 (Pyk2), a nonreceptor type protein tyrosine kinase, plays a crucial role in the pathogenesis of pulmonary hypertension (PH) using an animal model of hypoxia-induced PH. Resistance to hypoxia-induced PH was markedly higher in Pyk2-deficient mice than in wild-type mice. Pathological investigations revealed that medial thickening of the pulmonary arterioles, which is a characteristic of hypoxia-induced PH, was absent in Pyk2-deficient mice, suggesting that Pyk2 is involved in the hypoxia-induced aberrant proliferation of vascular smooth muscle cells in hypoxia-induced PH. In vitro experiments using human pulmonary smooth muscle cells showed that hypoxic stress increased the proliferation and migration of cells in a Pyk2-dependent manner. We also demonstrated that Pyk2 plays a crucial role in ROS generation during hypoxic stress and that this Pyk2-dependent generation of ROS is necessary for the activation of hypoxia-inducible factor-1α, a key molecule in the pathogenesis of hypoxia-induced PH. In summary, the results of the present study reveal that Pyk2 plays an important role in the pathogenesis of hypoxia-induced PH. Therefore, Pyk2 may represent a promising therapeutic target for PAH in a clinical setting.

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“…Moreover, we have previously demonstrated that loss of ARIA enhanced insulin sensitivity, as well as protected mice from diet-induced obesity and metabolic disorders by modulating endothelial insulin signaling and adipose tissue angiogenesis (27). Additionally, genetic loss of ARIA ameliorated doxorubicin-induced cardiomyopathy (21). These findings strongly suggest that ARIA is a unique and distinctive target for the prevention and/or treatment of cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 64%

“…ARIA is highly expressed in endothelial cells; therefore, loss of ARIA substantially enhanced angiogenesis by accelerating endothelial PI3K/Akt signaling. Moreover, we found a significant role of ARIA in the fine-tuning of PI3K/Akt signaling in cardiomyocytes (21). ARIA deficiency protects the heart from doxorubicin-induced cardiac dysfunction by reducing cardiomyocyte death due to enhanced cardiac PI3K/Akt signaling.…”

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confidence: 76%

“…These results suggest that ARIA has a potential role in the development of atherosclerosis by modulating macrophage functions. We previously reported that ARIA regulates PI3K/Akt signaling in endothelial cells and cardiomyocytes in a cell-autonomous fashion (20,21). Therefore, we examined whether ARIA regulates PI3K/Akt signaling in macrophages as well.…”

Section: Resultsmentioning

confidence: 99%

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Loss of Apoptosis Regulator through Modulating IAP Expression (ARIA) Protects Blood Vessels from Atherosclerosis

Matsuo

Akakabe

Kitamura

et al. 2015

Journal of Biological Chemistry

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Background: Macrophages play central roles in the whole process of atherosclerosis. Results: ARIA regulates macrophage foam cell formation at least in part by modulating ACAT-1 expression. Conclusion: ARIA is a novel factor involved in the pathogenesis of atherosclerosis. Significance: Loss of ARIA ameliorated atherosclerosis by reducing macrophage foam cell formation; inhibition of ARIA may represent a new line of therapy against atherosclerosis.

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Manipulation of Cardiac Phosphatidylinositol 3-Kinase (PI3K)/Akt Signaling by Apoptosis Regulator through Modulating IAP Expression (ARIA) Regulates Cardiomyocyte Death during Doxorubicin-induced Cardiomyopathy

Cited by 47 publications

References 44 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

Pyk2 aggravates hypoxia-induced pulmonary hypertension by activating HIF-1α

Loss of Apoptosis Regulator through Modulating IAP Expression (ARIA) Protects Blood Vessels from Atherosclerosis

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