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 language | English |
|---|---|
| Journal | JCI insight |
| Volume | 2 |
| Issue number | 15 |
| DOIs | |
| Publication status | Published - Aug 3 2017 |
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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 journal › Article
}
TY - JOUR
T1 - TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy
AU - Shimauchi, Tsukasa
AU - Numaga-Tomita, Takuro
AU - Ito, Tomoya
AU - Nishimura, Akiyuki
AU - Matsukane, Ryosuke
AU - Oda, Sayaka
AU - Hoka, Sumio
AU - Ide, Tomomi
AU - Koitabashi, Norimichi
AU - Uchida, Koji
AU - Sumimoto, Hideki
AU - Mori, Yasuo
AU - Nishida, Motohiro
PY - 2017/8/3
Y1 - 2017/8/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85054724619&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054724619&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.93358
DO - 10.1172/jci.insight.93358
M3 - Article
C2 - 28768915
AN - SCOPUS:85054724619
VL - 2
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 15
ER -