TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy

Shimauchi, Takashi; Numaga‐Tomita, Takuro; Ito, Tomoya; Nishimura, Akiyoshi; Matsukane, Ryosuke; Oda, Sayaka; Hoka, Sumio; Ide, Tomomi; Koitabashi, Norimichi; Uchida, Koji; Sumimoto, Hideki; Mori, Yasuo; Nishida, Motohiro

doi:10.1172/jci.insight.93358

Cited by 50 publications

(40 citation statements)

References 48 publications

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“…DOX treatment increased Nox2 protein abundance, which was significantly suppressed by the absence of TRPC3. TRPC3-knockout mouse hearts maintained both whole-heart and cross-sectional areas of cardiomyocytes [113]. Therefore, similar to mechanical overloading, TRPC3 can couple with Nox2 in DOX-induced cardiac atrophy.…”

Section: Cardiac Atrophymentioning

confidence: 89%

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TRPC Channels in Cardiac Plasticity

Numaga‐Tomita

Nishida

2020

Cells

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The heart flexibly changes its structure in response to changing environments and oxygen/nutrition demands of the body. Increased and decreased mechanical loading induces hypertrophy and atrophy of cardiomyocytes, respectively. In physiological conditions, these structural changes of the heart are reversible. However, chronic stresses such as hypertension or cancer cachexia cause irreversible remodeling of the heart, leading to heart failure. Accumulating evidence indicates that calcium dyshomeostasis and aberrant reactive oxygen species production cause pathological heart remodeling. Canonical transient receptor potential (TRPC) is a nonselective cation channel subfamily whose multimodal activation or modulation of channel activity play important roles in a plethora of cellular physiology. Roles of TRPC channels in cardiac physiology have been reported in pathological cardiac remodeling. In this review, we summarize recent findings regarding the importance of TRPC channels in flexible cardiac remodeling (i.e., cardiac plasticity) in response to environmental stresses and discuss questions that should be addressed in the near future.

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Section: Cardiac Atrophymentioning

confidence: 89%

“…In Nox2 -/mice, DOX-induced structural remodeling was completely attenuated [111]. DOX treatment has been shown to increase Nox2 expression in the heart [111][112][113]. Strikingly, the reduction of Nox2 expression by treatment with paeoniflorin suppressed DOX-induced cardiomyocyte apoptosis [112].…”

Section: Cardiac Atrophymentioning

confidence: 99%

TRPC Channels in Cardiac Plasticity

Numaga‐Tomita

Nishida

2020

Cells

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“…DOX is a powerful chemotherapy drug that can also cause damage to myocardial cells through a complex set of physiological effects when tumor cells are killed. The currently known mechanisms involved in DOX-induced cardiac injury include serious inflammatory responses, oxidative stress imbalance, severe myocardial cell autophagy, and apoptosis [9,[15][16][17][18]. The literature overwhelmingly suggests that myocardial cells can be directly damaged by an excessive inflammatory response, which exacerbates oxidative stress [9,15,[19][20][21], while severe or rapid autophagy can induce programmed myocardial cell death and decrease myocardial cell survival; however, autophagy has dual effects on myocardial cells, as mild autophagy partly protects cells from harmful conditions and promotes cell survival [22,23].…”

Section: Discussionmentioning

confidence: 99%

Thyroxine Alleviates Energy Failure, Prevents Myocardial Cell Apoptosis, and Protects against Doxorubicin-Induced Cardiac Injury and Cardiac Dysfunction via the LKB1/AMPK/mTOR Axis in Mice

et al. 2019

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Background. Previous studies have demonstrated that energy failure is closely associated with cardiac injury. Doxorubicin (DOX) is a commonly used clinical chemotherapy drug that can mediate cardiac injury through a variety of mechanisms. Thyroxine is well known to play a critical role in energy generation; thus, this study is aimed at investigating whether thyroxine can attenuate DOX-induced cardiac injury by regulating energy generation. Methods. First, the effect of DOX on adenosine diphosphate (ADP) and adenosine triphosphate (ATP) ratios in mice was assessed. In addition, thyroxine was given to mice before they were treated with DOX to investigate the effects of thyroxine on DOX-induced cardiac injury. Furthermore, to determine whether the liver kinase b1 (LKB1)/adenosine 5′-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) axis mediated the effect of thyroxine on DOX-induced cardiac injury, thyroxine was given to DOX-treated LKB1 knockout (KO) mice. Results. DOX treatment time- and dose-dependently increased the ADP/ATP ratio. Thyroxine treatment also reduced lactate dehydrogenase (LDH) and creatine kinase myocardial band (CK-MB) levels in both serum and heart tissue and alleviated cardiac dysfunction in DOX-treated mice. Furthermore, thyroxine reversed DOX-induced reductions in LKB1 and AMPK phosphorylation; mitochondrial complex I, III, and IV activity; and mitochondrial swelling and reversed DOX-induced increases in mTOR pathway phosphorylation and myocardial cell apoptosis. These effects of thyroxine on DOX-treated mice were significantly attenuated by LKB1 KO. Conclusions. Thyroxine alleviates energy failure, reduces myocardial cell apoptosis, and protects against DOX-induced cardiac injury via the LKB1/AMPK/mTOR axis in mice. Thyroxine may be a new agent for the clinical prevention of cardiac injury in tumor patients undergoing chemotherapy with DOX.

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“…or saline and killed 2 weeks later. The doses of doxorubicin and ibudilast were determined with reference to previous studies (Kagitani-Shimono et al, 2005;Poland, Hahn, Knapp, Beardsley, & Bowers, 2016;Shimauchi et al, 2017). Mice were killed by cervical dislocation, and tissues were removed and processed for histological examination or frozen for further analysis.…”

Section: Animal Modelmentioning

confidence: 99%

“…Recently, we reported that the extent of doxorubicin-induced formation of TRPC3-Nox2 complexes correlated well with the severity of doxorubicin-induced cardiac atrophy and that the inhibition of TRPC3-Nox2 physical interaction suppressed doxorubicin-induced myocardial atrophy in mice (Shimauchi et al, 2017). Thus, a drug already approved for clinical use which can also inhibit the formation of TRPC3-Nox2 complexes could be repurposed to prevent doxorubicin-induced adverse events.…”

Section: Introductionmentioning

confidence: 97%

Ibudilast attenuates doxorubicin‐induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes

Nishiyama

Numaga‐Tomita

Fujimoto

et al. 2019

British J Pharmacology

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Background and Purpose Doxorubicin is a highly effective anticancer agent but eventually induces cardiotoxicity associated with increased production of ROS. We previously reported that a pathological protein interaction between TRPC3 channels and NADPH oxidase 2 (Nox2) contributed to doxorubicin‐induced cardiac atrophy in mice. Here we have investigated the effects of ibudilast, a drug already approved for clinical use and known to block doxorubicin‐induced cytotoxicity, on the TRPC3‐Nox2 complex. We specifically sought evidence that this drug attenuated doxorubicin‐induced systemic tissue wasting in mice. Experimental Approach We used the RAW264.7 macrophage cell line to screen 1,271 clinically approved chemical compounds, evaluating functional interactions between TRPC3 channels and Nox2, by measuring Nox2 protein stability and ROS production, with and without exposure to doxorubicin. In male C57BL/6 mice, samples of cardiac and gastrocnemius muscle were taken and analysed with morphometric, immunohistochemical, RT‐PCR and western blot methods. In the passive smoking model, cells were exposed to DMEM containing cigarette sidestream smoke. Key Results Ibudilast, an anti‐asthmatic drug, attenuated ROS‐mediated muscle toxicity induced by doxorubicin treatment or passive smoking, by inhibiting the functional interactions between TRPC3 channels and Nox2, without reducing TRPC3 channel activity. Conclusions and Implications These results indicate a common mechanism underlying induction of systemic tissue wasting by doxorubicin. They also suggest that ibudilast could be repurposed to prevent muscle toxicity caused by anticancer drugs or passive smoking.

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TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy

Cited by 50 publications

References 48 publications

TRPC Channels in Cardiac Plasticity

TRPC Channels in Cardiac Plasticity

Thyroxine Alleviates Energy Failure, Prevents Myocardial Cell Apoptosis, and Protects against Doxorubicin-Induced Cardiac Injury and Cardiac Dysfunction via the LKB1/AMPK/mTOR Axis in Mice

Ibudilast attenuates doxorubicin‐induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes

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