TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling.
Reactive oxygen species (ROS) produced by NADPH oxidase 2 (Nox2) function as key mediators of mechanotransduction during both physiological adaptation to mechanical load and maladaptive remodeling of the heart. This is despite low levels of cardiac Nox2 expression. The mechanism underlying the transition from adaptation to maladaptation remains obscure, however. We demonstrate that transient receptor potential canonical 3 (TRPC3), a Ca2+-permeable channel, acts as a positive regulator of ROS (PRROS) in cardiomyocytes, and specifically regulates pressure overload-induced maladaptive cardiac remodeling in mice. TRPC3 physically interacts with Nox2 at specific C-terminal sites, thereby protecting Nox2 from proteasome-dependent degradation and amplifying Ca2+-dependent Nox2 activation through TRPC3-mediated background Ca2+entry. Nox2 also stabilizes TRPC3 proteins to enhance TRPC3 channel activity. Expression of TRPC3 C-terminal polypeptide abolished TRPC3-regulated ROS production by disrupting TRPC3-Nox2 interaction, without affecting TRPC3-mediated Ca2+influx. The novel TRPC3 function as a PRROS provides a mechanistic explanation for how diastolic Ca2+influx specifically encodes signals to induce ROS-mediated maladaptive remodeling and offers new therapeutic possibilities.
Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.|Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Naoyuki
N
Kitajima
Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.|Department of Physiological Sciences, SOKENDAI (School of Life Science, The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan.
Takuro
T
Numaga-Tomita
Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan.
Masahiko
M
Watanabe
Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan.
Takuya
T
Kuroda
Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.|Department of Physiological Sciences, SOKENDAI (School of Life Science, The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan.
Akiyuki
A
Nishimura
Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan.
Kei
K
Miyano
Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan.
Satoshi
S
Yasuda
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
Koichiro
K
Kuwahara
Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.|Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan.
Yoji
Y
Sato
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Tomomi
T
Ide
Laboratory of Neuroscience, NIEHS, NIH, Research Triangle Park, NC 27709, USA.|Institute for Biomedical Research (BIOMED), Catholic University of Argentina, C1107AFF Buenos Aires, Argentina.
Lutz
L
Birnbaumer
Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan.
Hideki
H
Sumimoto
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.
Yasuo
Y
Mori
Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.|Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.|Department of Physiological Sciences, SOKENDAI (School of Life Science, The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan.|PRESTO, JST, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
Motohiro
M
Nishida
D000818:Animals; D016466:CHO Cells; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D003412:Cricetulus; D003573:Cytochrome b Group / Q000378:metabolism; D003971:Diastole; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D000074662:NADPH Oxidase 2 / Q000378:metabolism; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025941:Protein Interaction Mapping; D055550:Protein Stability; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013314:Stress, Mechanical; D050052:TRPC Cation Channels / Q000172:deficiency / Q000502:physiology*; D000074287:TRPC6 Cation Channel; D018487:Ventricular Dysfunction, Left / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000502:physiology
D003573:Cytochrome b Group; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; C056558:CYBB protein, human; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C086986:CYBA protein, human; C515614:Cyba protein, mouse; D046988:Proteasome Endopeptidase Complex