TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy

Tsukasa Shimauchi, Takuro Numaga-Tomita, Tomoya Ito, Akiyuki Nishimura, Ryosuke Matsukane, Sayaka Oda, Sumio Hoka, Tomomi Ide, Norimichi Koitabashi, Koji Uchida, Hideki Sumimoto, Yasuo Mori, Motohiro Nishida

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Abstract

Myocardial atrophy is a wasting of cardiac muscle due to hemodynamic unloading. Doxorubicin is a highly effective anticancer agent but also induces myocardial atrophy through a largely unknown mechanism. Here, we demonstrate that inhibiting transient receptor potential canonical 3 (TRPC3) channels abolishes doxorubicin-induced myocardial atrophy in mice. Doxorubicin increased production of ROS in rodent cardiomyocytes through hypoxic stress-mediated upregulation of NADPH oxidase 2 (Nox2), which formed a stable complex with TRPC3. Cardiomyocyte-specific expression of TRPC3 C-terminal minipeptide inhibited TRPC3-Nox2 coupling and suppressed doxorubicin-induced reduction of myocardial cell size and left ventricular (LV) dysfunction, along with its upregulation of Nox2 and oxidative stress, without reducing hypoxic stress. Voluntary exercise, an effective treatment to prevent doxorubicin-induced cardiotoxicity, also downregulated the TRPC3-Nox2 complex and promoted volume load-induced LV compliance, as demonstrated in TRPC3-deficient hearts. These results illustrate the impact of TRPC3 on LV compliance and flexibility and, focusing on the TRPC3-Nox2 complex, provide a strategy for prevention of doxorubicin-induced cardiomyopathy.

Original languageEnglish
JournalJCI insight
Volume2
Issue number15
DOIs
Publication statusPublished - Aug 3 2017

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NADPH Oxidase
Doxorubicin
Atrophy
Cardiac Myocytes
Compliance
Up-Regulation
Left Ventricular Dysfunction
Cardiomyopathies
Cell Size
Antineoplastic Agents
Rodentia
Myocardium
Oxidative Stress
Down-Regulation
Hemodynamics

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TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy. / Shimauchi, Tsukasa; Numaga-Tomita, Takuro; Ito, Tomoya; Nishimura, Akiyuki; Matsukane, Ryosuke; Oda, Sayaka; Hoka, Sumio; Ide, Tomomi; Koitabashi, Norimichi; Uchida, Koji; Sumimoto, Hideki; Mori, Yasuo; Nishida, Motohiro.

In: JCI insight, Vol. 2, No. 15, 03.08.2017.

Research output: Contribution to journalArticle

Shimauchi, T, Numaga-Tomita, T, Ito, T, Nishimura, A, Matsukane, R, Oda, S, Hoka, S, Ide, T, Koitabashi, N, Uchida, K, Sumimoto, H, Mori, Y & Nishida, M 2017, 'TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy', JCI insight, vol. 2, no. 15. https://doi.org/10.1172/jci.insight.93358
Shimauchi, Tsukasa ; Numaga-Tomita, Takuro ; Ito, Tomoya ; Nishimura, Akiyuki ; Matsukane, Ryosuke ; Oda, Sayaka ; Hoka, Sumio ; Ide, Tomomi ; Koitabashi, Norimichi ; Uchida, Koji ; Sumimoto, Hideki ; Mori, Yasuo ; Nishida, Motohiro. / TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy. In: JCI insight. 2017 ; Vol. 2, No. 15.
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