The research groups led by Professor Nishida of Kyushu University, have previously reported that transient receptor potential canonical 3 (TRPC3) channels forms protein complex with Nox2 to stabilize and increase ROS generating activity in cardiac myocytes and fibroblasts, which leads to induction of interstitial fibrosis (i.e., deposition of collagen type I and III) and myocardial stiffness in mouse left ventricular (LV) myocardium (Figure 1).
Here, the groups demonstrate that inhibiting transient receptor potential canonical 3 (TRPC3) channels abolishes doxorubicin-induced myocardial atrophy in mice. Doxorubicin increased production of reactive oxygen species (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 mini-peptide inhibited TRPC3-Nox2 coupling and suppressed doxorubicin-induced reduction of myocardial cell size and LV dysfunction and its upregulation of Nox2 and oxidative stress, without reducing hypoxic stress (Figure 2).
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 (Figure 3). These results illustrate the impact of TRPC3 on LV compliance and flexibility and, focusing on the TRPC3-Nox2 complex, provide a new strategy for prevention of doxorubicin-induced cardiomyopathy.
Figure 1. Previous finding: TRPC3 positively regulates reactive oxygen species during maladaptive cardiac stiffness (fibrosis) in mice.
Figure 2. Doxorubicin (DOX) induces myocardial atrophy through upregulating TRPC3-Nox2 protein complex in mice.
Figure 3. Physiological role of TRPC3 in mouse heart. Deletion or inhibition of TRPC3 enhances cardiac compliance (i.e., flexibility and elastance) like modelate exercise-treated hearts.
Motohiro Nishida, Professor, Faculty of Pharmaceutical SciencesTsukasa Shimauchi, Assistant Professor, Kyushu University HospitalSumio Hoka, Professor, Faculty of Medical Sciences
Remarks：Hideki Sumimoto, Professor, Faculty of Medical Sciences
Tomomi Ide, Assistant Professor, Faculty of Medical Sciences