TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling

• Autores: Kitajima, Naoyuki; Numaga-Tomita, Takuro; Watanabe, Masahiko; Kuroda, Takuya; Nishimura, Akiyuki; Miyano, Kei; Yasuda, Satoshi; Kuwahara, Koichiro; Sato, Yoji; Ide, Tomomi; Birnbaumer, Lutz; Sumimoto, Hideki; Mori, Yasuo; Nishida, Motohiro
• Año de publicación: 2016
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: Scientific Reports. 2016;6:37001
• Materia: CALCIO; OXIGENO; ADAPTACION; PROTEINAS; CORAZON
• Institución: Pontificia Universidad Católica Argentina

Fil: Kitajima, Naoyuki. National Institute for Physiological Sciences. Division of Cardiocirculatory Signaling. Okazaki Institute for Integrative Bioscience; Japón
Fil: Kitajima, Naoyuki. Kyushu University. Graduate School of Pharmaceutical Sciences. Department of Translational Pharmaceutical Sciences; Japón
Fil: Numaga-Tomita, Takuro. National Institute for Physiological Sciences. Division of Cardiocirculatory Signaling. Okazaki Institute for Integrative Bioscience; Japón
Fil: Numaga-Tomita, Takuro. The Graduate University for Advanced Studies. School of Life Science. Department of Physiological Sciences; Japón
Fil: Watanabe, Masahiko. Hokkaido University School of Medicine. Department of Anatomy; Japón
Fil: Kuroda, Takuya. National Institute of Health Sciences. Division of Cell-Based Therapeutic Products; Japón
Fil: Nishimura, Akiyuki. National Institute for Physiological Sciences. Division of Cardiocirculatory Signaling. Okazaki Institute for Integrative Bioscience; Japón
Fil: Nishimura, Akiyuki. The Graduate University for Advanced Studies. School of Life Science. Department of Physiological Sciences; Japón
Fil: Miyano, Kei. Kyushu University. Graduate School of Medical Sciences. Department of Biochemistry; Japón
Fil: Yasuda, Satoshi. National Institute of Health Sciences. Division of Cell-Based Therapeutic Products; Japón
Fil: Kuwahara, Koichiro. Kyoto University. Graduate School of Medicine. Department of Cardiovascular Medicine; Japón
Fil: Sato, Yoji. Kyushu University. Graduate School of Pharmaceutical Sciences. Department of Translational Pharmaceutical Sciences; Japón
Fil: Sato, Yoji. National Institute of Health Sciences. Division of Cell-Based Therapeutic Products; Japón
Fil: Ide, Tomomi. Kyushu University. Department of Cardiovascular Medicine. Graduate School of Medical Sciences; Japón
Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences. Laboratory of Neuroscience; Estados Unidos
Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Sumimoto, Hideki. Kyushu University. Graduate School of Medical Sciences. Department of Biochemistry; Japón
Fil: Mori, Yasuo. Kyoto University. Graduate School of Engineering. Department of Synthetic Chemistry and Biological Chemistry; Japón
Fil: Nishida, Motohiro. National Institute for Physiological Sciences. Division of Cardiocirculatory Signaling. Okazaki Institute for Integrative Bioscience; Japón
Fil: Nishida, Motohiro. Kyushu University. Graduate School of Pharmaceutical Sciences. Department of Translational Pharmaceutical Sciences; Japón
Fil: Nishida, Motohiro. The Graduate University for Advanced Studies. School of Life Science. Department of Physiological Sciences; Japón
Fil: Nishida, Motohiro. Precursory Research for Embryonic Science and Technology; Japón
Abstract: 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.