著者

Hirofumi Tsuru Hidekazu Ishida Jun Narita Ryo Ishii Hidehiro Suginobe Yoichiro Ishii Renjie Wang Shigetoyo Kogaki Masaki Taira Takayoshi Ueno Yohei Miyashita Hidetaka Kioka Yoshihiro Asano Yoshiki Sawa Keiichi Ozono

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.85, no.5, pp.677-686, 2021-04-23 (Released:2021-04-23)

参考文献数

38

被引用文献数

9

---

Background:Restrictive cardiomyopathy (RCM) is characterized by impaired ventricular relaxation. Although several mutations were reported in some patients, no mutations were identified in cardiomyocyte expressing genes of other patients, indicating that pathological mechanisms underlying RCM could not be determined by cardiomyocytes only. Cardiac fibroblasts (CFs) are a major cell population in the heart; however, the pathological roles of CFs in cardiomyopathy are not fully understood.Methods and Results:This study established 4 primary culture lines of CFs from RCM patients and analyzed their cellular physiology, the effects on the contraction and relaxation ability of healthy cardiomyocytes under co-culture with CFs, and RNA sequencing. Three of four patients hadTNNI3mutations. There were no significant alterations in cell proliferation, apoptosis, migration, activation, and attachment. However, when CFs from RCM patients were co-cultured with healthy cardiomyocytes, the relaxation velocity of cardiomyocytes was significantly impaired both under direct and indirect co-culture conditions. RNA sequencing revealed that gene expression profiles of CFs in RCM were clearly distinct from healthy CFs. The differential expression gene analysis identified that several extracellular matrix components and cytokine expressions were dysregulated in CFs from RCM patients.Conclusions:The comprehensive gene expression patterns were altered in RCM-derived CFs, which deteriorated the relaxation ability of cardiomyocytes. The specific changes in extracellular matrix composition and cytokine secretion from CFs might affect pathological behavior of cardiomyocytes in RCM.

著者

Hirokai Kitaoka Hiroyuki Tsutsui Toru Kubo Tomomi Ide Taishiro Chikamori Keiichi Fukuda Noboru Fujino Taiki Higo Mitsuaki Isobe Chizuko Kamiya Seiya Kato Yasuki Kihara Koichiro Kinugawa Shintaro Kinugawa Shigetoyo Kogaki Issei Komuro Nobuhisa Hagiwara Minoru Ono Yuichiro Maekawa Shigeru Makita Yoshiro Matsui Shouji Matsushima Yasushi Sakata Yoshiki Sawa Wataru Shimizu Kunihiko Teraoka Miyuki Tsuchihashi-Makaya Hatsue Ishibashi-Ueda Masafumi Watanabe Michihiro Yoshimura Arata Fukusima Satoshi Hida Shungo Hikoso Teruhiko Imamura Hiroko Ishida Makoto Kawai Toshiro Kitagawa Takashi Kohno Satoshi Kurisu Yoji Nagata Makiko Nakamura Hiroyuki Morita Hitoshi Takano Tsuyoshi Shiga Yasuyoshi Takei Shinsuke Yuasa Teppei Yamamoto Tetsu Watanabe Takashi Akasaka Yoshinori Doi Takeshi Kimura Masafumi Kitakaze Masami Kosuge Morimasa Takayama Hitonobu Tomoike on behalf of the Japanese Circulation Society Joint Working Group

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

pp.CJ-20-0910, (Released:2021-07-22)

参考文献数

687

被引用文献数

47

著者

Hiroaki Ichimori Shigetoyo Kogaki Kunihiko Takahashi Hidekazu Ishida Jun Narita Nobutoshi Nawa Hiroki Baden Toshiki Uchikawa Yoko Okada Keiichi Ozono

出版者

日本循環器学会

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

pp.CJ-12-0997, (Released:2013-05-18)

参考文献数

37

被引用文献数

5 8

---

Background: To investigate the possible role of sex hormones in the pathogenesis of pulmonary arterial hypertension (PAH), the effect of β-estradiol (E2) on bone morphogenetic protein (BMP) signaling, a key signaling pathway involved in PAH, was studied in human pulmonary arterial endothelial cells (HPAEC). Methods and Results: BMP signaling molecules, including BMP receptor, Smad1/5/8 and Id1, were studied in HPAEC under 1% O2 (hypoxia) and 21% O2 (normoxia) as well as the effect of hypoxia-inducible factor (HIF)-1α expression in the presence of E2 on BMP signaling. The effects of an estrogen receptor (ER) antagonist (ICI 182,780) and cycloheximide, and the interaction of ER with Smad or HIF-1α were also studied. In the presence of E2, BMP signaling was augmented under normoxia but suppressed under hypoxia. HIF-1α accumulation suppressed BMP signaling, whereas HIF-1α inhibition augmented signaling. These effects were cancelled by ICI 182,780. Moreover, binding between ER, HIF-1α and phosphorylated (p)-Smad1/5/8 proteins occurred only under hypoxia. On inhibition of de novo synthesis with cycloheximide, however, p-Smad1/5/8 expression was suppressed only under normoxia. Conclusions: The effects of E2 on BMP signaling in HPAEC altered depending on O2 concentration and different mechanisms may be involved. BMP and sex hormones may play an important role in PAH development.