Roles of Voltage- and cation-independent TRPC channels in cardiac hypertrophy

• Project/Area Number: 20390025
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Kyushu University
• Principal Investigator: KUROSE Hitoshi Kyushu University, 大学院・薬学研究院・薬効安全性学, 教授 (10183039)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000); Fiscal Year 2010: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2009: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2008: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
• Keywords: 心肥大 / TRPCチャネル / リン酸化 / cGMP / ホスホジエステラーゼ阻害剤 / 圧負荷 / cGMP依存性タンパク質リン酸化酵素 / ホスホジエステラーゼ5阻害剤 / 圧負荷ストレス / cAMP依存性リン酸化酵素 / cGMP依存性リン酸化酵素 / 細胞内Ca^<2+>制御 / 選択的阻害剤 / 化合物Pyr3 / 圧負荷モデル

Research Abstract

We have reported that angiotensin II or endothelin-1 stimulation induce hypertrophic responses through transient receptor potential canonical channel 3 (TRPC3) and TRPC6-mediated Ca2+ influx using rat neonatal cardiomyocytes. TRPC3/TRPC6 are voltage-independent and cation-non-selective ion channels, and activated by diacylglycerol generated by Gq-stimulated phospholipase C activation. However, these results were obtained from in vitro cell system using receptor stimulation of cardiomyocytes isolated from newborn rats. It is essential to demonstrate the importance of TRPC3/TRPC6 in in vivo hypertrophy model. Therefore, we have examined whether TRPC3/TRPC6 are involved in pressure overload-induced cardiac hypertrophy. Pressure overload is considered as a mouse model of chronic human hypertension, and induces cardiac hypertrophy. As the compound Pyr3 that selectively inhibits TRPC3 was available, we obtained it and administered to pressure overloaded mice. Pressure overload is applied by transverse aortic constriction procedure (TAC), and Pyr3 is administered by osmotic mini-pump. Pressure overload-induced hypertrophy was inhibited in Pyr3-treated mice as compare to wild type mice, which was as assessed by increased size of cardiomyocytes and increased expression of ANP. Furthermore, cardiac function such as fractional shortening is improved by the treatment with Pyr3. Next, we also examined the involvement of TRPC6 in pressure overload-induced cardiac hypertrophy. As the function of TRPC6 is inhibited by phosphorylation of TRPC6, we used a cGMP-selective phosphodiesterase (phosphodiesterase type 5:PDE5) inhibitor, sildenafil, for the increase in cardiac cGMP content. The treatment with sildenafil inhibited cardiac hypertrophy by pressure overload. The increased expression of various marker genes of hypertrophy was inhibited by the treatment with sildenafil. In sidenafil-treated mice, anti-phospho-TRPC6 antibody revealed that TRPC6 was phosphorylated at a specific site that is essential for TRPC6-mediated Ca^<2+> influx. These results suggest that TRPC3/TRPC6-mediated Ca^<2+> influx plays an important role in cardiac hypertrophy in vivo as well as in vitro.

Research Products

• [Journal Article] Phosphorylation of TRPC6 channels at Thr69 is required for anti-hypertrophic effects of phosphodiesterase 5 inhibition. (2010)
  • Author(s): Nishida M, Watanabe K, Sato Y, Nakaya M, Kitajima N, Ide T, Inoue R, Kurose H.
  • Journal Title: J Biol Chem. 286(17) Pages: 13244-13253
• [Journal Article] inhibition of TRPC6 channel actvitiy contributes to the antihypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart. (2010)
  • Author(s): Kinoshita H, Kuwahara K, Nishida M, Jiang Z, Rong X, Kiyonaka S, Kuwabara Y, Kurose H, Inoue R, Mori Y, Nakagawa Y, Usami S, Fujiwara M, Yamada Y, Minami T, Ueshima K, Nakao K.
  • Journal Title: Circ Res. 106(12) Pages: 1849-1860
• [Journal Article] Phosphorylation of TRPC6 channels at Thr69 is required for anti-hypertrophic effects of phosphodiesterase 5 inhibition. (2010)
  • Author(s): Nishida M, Watanabe K, Sato Y, Nakaya M, Kitajima N, Ide T, Inoue R, Kurose H.
  • Journal Title: Journal of Biological Chemistry Volume: 286 Pages: 13244-13253
  • Peer Reviewed
• [Journal Article] Inhibition of TRPC6 channel actvitiy contributes to the antihypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart. (2010)
  • Author(s): Kinoshita H, Kuwahara K, Nishida M, Jiang Z, Rong X, Kiyonaka S, Kuwabara Y, Kurose H, Inoue R, Mori Y, Nakagawa Y, Usami S, Fujiwara M, Yamada Y, Minami T, Ueshima K, Nakao K.
  • Journal Title: Circulation Research Volume: 106 Pages: 1849-1860
  • Peer Reviewed
• [Journal Article] Pertussis toxin up-regulates angiotensin type 1 receptors through Toll-like receptor 4-mediated Rac activation. (2010)
  • Author(s): Nishida M, Suda R, Nagamatsu Y, Tanabe S, Onohara N, Nakaya M, Kanaho Y, Shibata T, Uchida K, Sumimoto H, Sato Y, Kurose H.
  • Journal Title: Journal of Biological Chemistry Volume: 286 Pages: 15268-15277
  • Peer Reviewed
• [Journal Article] Agonist-induced endocytosis and receptor phosphorylation mediate resensitization of dopamine D_2 receptors. (2010)
  • Author(s): Cho D, Zheng M, Min C, Ma L, Kurose H, Park JH, Kim KM.
  • Journal Title: Mol Endocrinol. 24 Pages: 574-586
  • Peer Reviewed
• [Journal Article] Divergent roles of prokineticin receptors in the endothelial cells : angiogenesis and fenestration. (2010)
  • Author(s): Guilini C, Urayama K, Turkeri G, Dedeoglu DB, Kurose H, Messaddeq N, Nebigil CG.
  • Journal Title: Am J Physiol Heart Circ Physiol. 298
  • Peer Reviewed
• [Journal Article] Mechanism and role of high density lipoprotein-induced activation of AMP-activated protein kinase in endothelial cells. (2010)
  • Author(s): Kimura T, Tomura H, Sato K, Ito M, Matsuoka I, Im DS, Kuwabara A, Mogi C, Itoh H, Kurose H, Murakami M, Okajima F.
  • Journal Title: J Biol Chem. 285 Pages: 4387-4397
  • Peer Reviewed
• [Journal Article] Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound. (2009)
  • Author(s): Kiyonaka, S., Kato, K., Nishida, M., Mio, K., Numaga, T., Sawaguchi, Y., Yoshida, T., Wakamori, M., Mori, E., Numata, T., Ishii, M., Takemoto, H., Ojida, A., Watanabe, K., Uemura, A., Kurose, H., Morii, T., Kobayashi. T., Sato, Y., Sato, C., Hamachi, I., Mori, Y.
  • Journal Title: Proc.Natl.Acad.Sci.USA 106(13) Pages: 5400-5405
• [Journal Article] Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound. (2009)
  • Author(s): Kiyonaka, S., Kato, K., Nishida, M., Mio, K., Numaga, T., Sawaguchi, Y., Yoshida, T., Wakamori, M., Mori, E., Numata, T, Ishii, M., Takemoto, H., Ojida, A., Watanabe, K., Uemura, A., Kurose, H., Morii, T., Kobayashi. T., Sato, Y., Sato, C, Hamachi, I., Mori, Y.
  • Journal Title: Proceedings of the National Academy of Sciences of the USA 106巻 Pages: 5400-5405
  • Peer Reviewed
• [Journal Article] Keapl regulates the constitutive expression of GST Al during differentiation of Caco-2 cells. (2008)
  • Author(s): Kusano, Y, Horie, S., Shibata, T, Satsu, H., Shimizu, M, Hitomi, E., Nishida, M., Kurose, H., Itoh, K., Kobayashi, A., Yamamoto, M., Uchida, K.
  • Journal Title: Biochemistry 47 Pages: 6169-6177
  • Peer Reviewed
• [Journal Article] βγ subunits of Gi/o suppress EGF-induced ERK5 phosphorylation, whereas ERK1/2 phosphorylation is enhanced. (2008)
  • Author(s): Obara, Y, Okano, Y, Ono, S., Yamauchi, A., Hoshino, T., Kurose, H., Nakahata, N.
  • Journal Title: Cellular Signaling 20 Pages: 1275-1283
  • Peer Reviewed
• [Presentation] 心臓の線維化 (2010)
  • Author(s): 黒瀬等
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートピアホテル
  • Year and Date: 2010-12-08
• [Presentation] 心臓の線維化 (2010)
  • Author(s): 黒瀬等
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会 合同大会
  • Place of Presentation: シンポジウム
• [Presentation] βアドレナリン受容体遮断薬によるGRK5/βアレスチン2を介した心臓の線維化 (2010)
  • Author(s): 仲矢道雄、西田基宏、黒瀬等
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: シンポジウム
• [Presentation] βアドレナリン受容体遮断薬のGRK5/βアレスチン2を介した心臓の線維化 (2010)
  • Author(s): 仲矢道雄、西田基宏、黒瀬等
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: シンポジウム
• [Presentation] 転写因子のシステイン修飾による受容体発現の調節機構 (2009)
  • Author(s): 黒瀬等、西田基宏、大串真理、須田玲子、仲矢道雄
  • Organizer: 第82回 日本生化学会大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2009-10-23
• [Presentation] 線維化とプリン受容体 (2009)
  • Author(s): 黒瀬等
  • Organizer: 日本薬学会第129年会
  • Place of Presentation: シンポジウム
• [Presentation] 受容体・TRPCチャネル機能連関による心肥大シグナル制御 (2008)
  • Author(s): 西田基宏, 仲矢道雄, 黒瀬等
  • Organizer: 薬理学会共催・トランスポーター研究会
  • Place of Presentation: 福岡大学
  • Year and Date: 2008-11-02
• [Presentation] 心臓の線維化におけるG_<12/13>蛋白質の役割 (2008)
  • Author(s): 黒瀬等、西田基宏
  • Organizer: 薬理学会共催・第2回トランスポーター研究会
  • Place of Presentation: シンポジウム ワークショップin福岡
• [Presentation] 抗血小板薬シロスタゾールのTRPCチャネルの抑制を介した血管拡張作用 (2008)
  • Author(s): 有吉麻里奈、西岡絹恵、仲矢道雄、西田基宏、黒瀬等
  • Organizer: 薬理学会共催・第2回トランスポーター研究会 ポスター発表
  • Place of Presentation: ワークショップin福岡
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