TY - JOUR
T1 - The actin-organizing formin protein Fhod3 is required for postnatal development and functional maintenance of the adult heart in mice
AU - Ushijima, Tomoki
AU - Fujimoto, Noriko
AU - Matsuyama, Sho
AU - Kan-O, Meikun
AU - Kiyonari, Hiroshi
AU - Shioi, Go
AU - Kage, Yohko
AU - Yamasaki, Sho
AU - Takeya, Ryu
AU - Sumimoto, Hideki
N1 - Funding Information:
Acknowledgments—We thank Masato Tanaka (Kyushu University) for manipulation of mouse embryos; Kanako Motomura (Kyushu University) for histological analysis; Ryo Ugawa (Kyushu University) for transmission electron microscopic analysis; Drs. Atsushi Yamashita and Yujiro Asada (University of Miyazaki) for polarization microscopic analysis; Shoko Miura (Kyushu University) and Ami Matsuda (Miyazaki University) for technical assistance. We also appreciate the technical support from the Research Support Center, Research Center for Human Disease Modeling, Kyushu University Graduate School of Medical Sciences, and the Laboratory for Technical Support, Medical Institute of Bioregulation, Kyushu University.
Funding Information:
This work was supported in part by Grant-in-aid for Scientific Research on Innovative Areas “Oxygen Biology: a new criterion for integrated under-standing of life” Grant 26111009 (to H. S.), Japan Society for the Promotion of Science (JSPS) KAKENHI Grant 26460371 (to R. T.), SHINGAKUJUTSU Grant 25117515 (to R. T.), grants from the Takeda Science Foundation (to R. T.) and the Institute of Seizon and Life Sciences (to R. T.), and the Coop-erative Research Project Program of the Medical Institute of Bioregulation, Kyushu University (to R. T.). The authors declare that they have no conflicts of interest with the contents of this article.
Publisher Copyright:
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2018/1/5
Y1 - 2018/1/5
N2 - Cardiac development and function require actin-myosin interactions in the sarcomere, a highly organized contractile structure. Sarcomere assembly mediated by formin homology 2 domain-containing 3 (Fhod3), a member of formins that directs formation of straight actin filaments, is essential for embryonic cardiogenesis. However, the role of Fhod3 in the neonatal and adult stages has remained unknown. Here, we generated floxed Fhod3 mice to bypass the embryonic lethality of an Fhod3 knockout (KO). Perinatal KO of Fhod3 in the heart caused juvenile lethality at around day 10 after birth with enlarged hearts composed of severely impaired myofibrils, indicating that Fhod3 is crucial for postnatal heart development. Tamoxifeninduced conditional KO of Fhod3 in the adult heart neither led to lethal effects nor did it affect sarcomere structure and localization of sarcomere components. However, adult Fhod3-deleted mice exhibited a slight cardiomegaly and mild impairment of cardiac function, conditions that were sustained over 1 year without compensation during aging. In addition to these agerelated changes, systemic stimulation with the α1-adrenergic receptor agonist phenylephrine, which induces sustained hypertension and hypertrophy development, induced expression of fetal cardiac genes that was more pronounced in adult Fhod3- deleted mice than in the control mice, suggesting that Fhod3 modulates hypertrophic changes in the adult heart. We conclude that Fhod3 plays a crucial role in both postnatal cardiac development and functional maintenance of the adult heart.
AB - Cardiac development and function require actin-myosin interactions in the sarcomere, a highly organized contractile structure. Sarcomere assembly mediated by formin homology 2 domain-containing 3 (Fhod3), a member of formins that directs formation of straight actin filaments, is essential for embryonic cardiogenesis. However, the role of Fhod3 in the neonatal and adult stages has remained unknown. Here, we generated floxed Fhod3 mice to bypass the embryonic lethality of an Fhod3 knockout (KO). Perinatal KO of Fhod3 in the heart caused juvenile lethality at around day 10 after birth with enlarged hearts composed of severely impaired myofibrils, indicating that Fhod3 is crucial for postnatal heart development. Tamoxifeninduced conditional KO of Fhod3 in the adult heart neither led to lethal effects nor did it affect sarcomere structure and localization of sarcomere components. However, adult Fhod3-deleted mice exhibited a slight cardiomegaly and mild impairment of cardiac function, conditions that were sustained over 1 year without compensation during aging. In addition to these agerelated changes, systemic stimulation with the α1-adrenergic receptor agonist phenylephrine, which induces sustained hypertension and hypertrophy development, induced expression of fetal cardiac genes that was more pronounced in adult Fhod3- deleted mice than in the control mice, suggesting that Fhod3 modulates hypertrophic changes in the adult heart. We conclude that Fhod3 plays a crucial role in both postnatal cardiac development and functional maintenance of the adult heart.
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U2 - 10.1074/jbc.M117.813931
DO - 10.1074/jbc.M117.813931
M3 - Article
C2 - 29158260
AN - SCOPUS:85040126600
SN - 0021-9258
VL - 293
SP - 148
EP - 162
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 1
ER -