Elucidation of MURC-mediated mechanisms of caveolae function and transportsome formation in cardiomyocytes

• Project/Area Number: 23591088
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: UEYAMA Tomomi 京都府立医科大学, 医学(系)研究科(研究院), 講師 (80379388)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 心肥大 / カベオラ / 心筋細胞 / MURC / cavin family

Research Abstract

Immunoelectron microscopy revealed that MURC was expressed in caveolae and T tubules in cardiomyocytes, and transmission electron microscopy showed that caveolae were retained in cardiomyocytes of MURC-knockout (KO) mice. Alpha-1 adrenergic receptor (AR) stimulation-induced ERK activation and cardiac hypertrophy were attenuated in MURC-KO mice compared with wild-type mice. Upon alpha-1-AR stimulation, both MURC and phosphorylated ERK were translocated from the plasma membrane to the perinuclear region in cardiomyocytes. Immunoprecipitation revealed that MURC was associated with phosphorylated and total ERK. These findings suggest that MURC is dispensable for caveolar formation in cardiomyocytes, and that MURC serves as an ERK-recruiting protein in the caveolae within cardiomyocytes. The recruiting function of MURC is necessary to elicit efficient signaling of the alpha-1-AR/ERK cascade in the caveolae in cardiac hypertrophy.

Research Products

• [Journal Article] MURC/Cavin-4 facilitates recruitment of ERK to caveolae and concentric cardiac hypertrophy induced byα1-adrenergic receptors (2014)
  • Author(s): Ogata T, Naito D, Nakanishi N, Hayashi YK, Taniguchi T, Miyagawa K, Hamaoka T, Maruyama N, Matoba S, Ikeda K, Yamada H, Oh H, Ueyama T
  • Journal Title: Proc Natl Acad Sci U S A Volume: 111 Pages: 3811-3816
• [Journal Article] MURC/Cavin-4 facilitates recruitment of ERK to caveolae and concentric cardiac hypertrophy induced by α1-adrenergic receptors. (2014)
  • Author(s): Ogata T, Naito D, Nakanishi N, Hayashi YK, Taniguchi T, Miyagawa K, Hamaoka T, Maruyama N, Matoba S, Ikeda K, Yamada H, Oh H, Ueyama T.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 111 Issue: 10 Pages: 3811-3816
  • DOI: 10.1073/pnas.1315359111
  • Peer Reviewed / Open Access
• [Journal Article] Serglycin is a novel adipocytokine highly expressed in epicardial adipose tissue (2013)
  • Author(s): Imoto-Tsubakimoto H, Takahashi T, Ueyama T, Ogata T, Adachi A, Nakanishi N, Mizushima K, Naito Y, Matsubara H
  • Journal Title: Biochem Biophys Res Commun Volume: 423 Pages: 105-110
• [Journal Article] PARM-1 promotes cardiomyogenic differentiation through regulating the BMP/Smad signaling pathway (2013)
  • Author(s): Nakanishi N, Takahashi T, Ogata T, Adachi A, Imoto-Tsubakimoto H, Ueyama T, Matsubara H
  • Journal Title: Biochem Biophys Res Commun Volume: 428 Pages: 500-505
• [Journal Article] NFAT5 regulates the canonical Wnt pathway and is required for cardiomyogenic differentiation (2012)
  • Author(s): Adachi A, Takahashi T, Ogata T, Imoto-Tsubakimoto H, Nakanishi N, Ueyama T, Matsubara H
  • Journal Title: Biochem Biophys Res Commun Volume: 426 Pages: 317-323
• [Journal Article] Molecular genetic and functional characterization implicate muscle-restricted coiled-coil gene (MURC) as a causal gene for familial dilated cardiomyopathy (2011)
  • Author(s): Rodriguez G, Ueyama T, Ogata T, Czernuszewicz G, Tan Y, Dorn GW 2nd, Bogaev R, Amano K, Oh H, Matsubara H, Willerson JT, Marian AJ
  • Journal Title: Circ Cardiovasc Genet Volume: 4 Pages: 349-358
• [Journal Article] Early Inflammatory Reactions in Atherosclerosis Are Induced by Tyrosine Kinase Proline-Rich Tyrosine Kinase/Reactive Oxygen Species-Mediated Release of Tumor Necrosis Factor-α and Subsequent Activation of the p21Cip1/Ets-1/p300 System. (2011)
  • Author(s): Katsume A, Okigaki M, Matsui A, Che J, Adachi Y, Kishita E, Yamaguchi S, Ikeda K, Ueyama T, Matoba S, Yamada H, Matsubara H.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 31 Issue: 5 Pages: 1084-1092
  • DOI: 10.1161/atvbaha.110.221804
  • Peer Reviewed
• [Journal Article] Apoptosis regulator through modulating IAP expression (ARIA) controls the PI3K/Akt pathway in endothelial and endothelial progenitor cells (2011)
  • Author(s): Koide M, et al
  • Journal Title: Proc Natl Acad Sci U S A Volume: 108 Issue: 23 Pages: 9472-9477
  • DOI: 10.1073/pnas.1101296108
  • Peer Reviewed
• [Journal Article] Molecular Genetic and Functional Characterization Implicate Muscle-Restricted Coiled-Coil Gene (MURC) as a Causal Gene for Familial Dilated Cardiomyopathy (2011)
  • Author(s): Rodriguez G, et al
  • Journal Title: Circ Cardiovasc Genet Volume: 4 Issue: 4 Pages: 349-358
  • DOI: 10.1161/circgenetics.111.959866
  • Peer Reviewed
• [Journal Article] Loss of bcl-2 during the senescence exacerbates the impaired angiogenic functions in endothelial cells by deteriorating the mitochondrial redox state. (2011)
  • Author(s): Uraoka M, Ikeda K, Kurimoto-Nakano R, Nakagawa Y, Koide M, Akakabe Y, Kitamura Y, Ueyama T, Matoba S, Yamada H, Okigaki M, Matsubara H.
  • Journal Title: Hypertension. Volume: 58 Issue: 2 Pages: 254-263
  • DOI: 10.1161/hypertensionaha.111.176701
  • Peer Reviewed
• [Presentation] MURC/Cavin-4 deficiency alleviates pulmonary arterial hypertension (2014)
  • Author(s): Nakanishi N, Ogata T, Maruyama N, Miyagawa K, Hamaoka T, Ueyama T
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京都
• [Presentation] Genetic deletion of MURC/Cavin-4 aggravates abdominal aortic aneurysm (2014)
  • Author(s): Miyagawa K, Ogata T, Nakanishi N, Hamaoka T, Maruyama N, Ueyama T
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京都
• [Presentation] SDPR/Cavin-2 prevents cardiomyocyte hypertrophy through the inhibition of Akt signaling (2014)
  • Author(s): Maruyama N, Ogata T, Nakanishi N, Miyagawa K, Hamaoka T, Ueyama T
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京都
• [Presentation] MURC/Cavin-4 modulates caveolin-3 function and regulates cardiac function (2014)
  • Author(s): Hamaoka T, Naito D, Ogata T, Nakanishi N, Miyagawa K, Maruyama N, T Shirayama, Ueyama T
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京都
• [Presentation] MURC/cavin-4 modulates caveolin-3 function and regulates cardiac function. (2014)
  • Author(s): Hamaoka T, Naito D, Ogata T, Nakanishi N, Miyagawa K, Maruyama N, T Shirayama, Ueyama T.
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京都
• [Presentation] Deficiency of MURC/Cavin-4 alleviates pulmonary arterial hypertension (2013)
  • Author(s): Nakanishi N, Ogata T, Miyagawa K, Hamaoka T, Maruyama N, Ueyama T
  • Organizer: American Heart Association Scientific Session 2013
  • Place of Presentation: Dallas, USA
• [Presentation] MURC promotes recruitment of ERK1/2 to caveolae of the plasma membrane and concentric cardiac hypertrophy induced byα1-adrenergic stimulation (2013)
  • Author(s): Ogata T, Nakanishi N, Miyagawa K, Hamaoka T, Maruyama N, Ueyama T
  • Organizer: American Heart Association Scientific Session 2013
  • Place of Presentation: Dallas, USA
• [Presentation] Genetic deletion of MURC/cavin-4 aggravates abdominal aortic aneurysm (2013)
  • Author(s): Miyagawa K, Ogata T, Nakanishi N, Hamaoka T, Maruyama N, Ueyama T
  • Organizer: American Heart Association Scientific Session 2013
  • Place of Presentation: Dallas, USA
• [Presentation] MURC/Cavin-4 negatively regulates protective effects of caveolin-3 in cardiac function (2013)
  • Author(s): Naito D, Ueyama T, Kobara M, Amano K, Ogata T, Taniguchi T, Nakanishi N, Miyagawa K, Matsubara H
  • Organizer: 第77回日本循環器学会学術集会
  • Place of Presentation: 神奈川県
• [Presentation] MURC/Cavin-4, a muscle-specific caveolae-related protein, mediates the development of pulmonary arterial hypertension though enhanced Gα13/p115RhoGEF/RhoA signaling (2013)
  • Author(s): Nakanishi N, Ogata T, Miyagawa K, Naito D, Taniguchi T, Ueyama T, Matsubara H
  • Organizer: 第77回日本循環器学会学術集会
  • Place of Presentation: 神奈川県
• [Presentation] MURC/Cavin-4, a Muscle-restricted caveolar scaffolding protein for activated ERK, regulates cardiac hypertrophy induced byα1-adrenergic agonist (2013)
  • Author(s): Ogata T, Ueyama T, Naito D, Nakanishi N, Taniguchi T, Miyagawa K, Hamaoka T, Matsubara H
  • Organizer: 第77回日本循環器学会学術集会
  • Place of Presentation: 神奈川県
• [Presentation] MURC regulates Rho/ROCK signaling in vascular smooth muscle cells and mediates the development of pulmonary arterial hypertension (2013)
  • Author(s): Nakanishi N, Ogata T, Miyagawa K, Hamaoka T, Maruyama N, Ueyama T
  • Organizer: 第21回日本血管生物学会学術集会
  • Place of Presentation: 大阪府
• [Presentation] MURC/Cavin-4 has a protective role in the progression of abdominal aortic aneurysm (2013)
  • Author(s): Miyagawa K, Ogata T, Nakanishi N, Hamaoka T, Maruyama N, Ueyama T
  • Organizer: 第21回日本血管生物学会学術集会
  • Place of Presentation: 大阪府
• [Presentation] MURC Promotes Recruitment of Erk1/2 to Caveolae of The Plasma Membrane and Concentric Cardiac Hypertrophy Induced by α1-adrenergic Stimulation. (2013)
  • Author(s): Ogata T, Nakanishi N, Miyagawa K, Hamaoka T, Maruyama N, Ueyama.
  • Organizer: American Heart Association Scientific Sessions 2013
  • Place of Presentation: Dallas, USA
• [Presentation] MURC/Cavin-4 Negatively Regulates Protective Effects of Caveolin-3 in Cardiac Function. (2013)
  • Author(s): Naito D, et al.
  • Organizer: 第77回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] MURC/Cavin-4, a Muscle-restricted Caveolar Scaffolding Protein for Activated ERK, Regulates Cardiac Hypertrophy Induced by α1-Adrenergic Agonist. (2013)
  • Author(s): Ogata T, et al.
  • Organizer: 第77回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] MURC/Cavin-4, a muscle-specific caveolae-related protein, mediates the development of pulmonary arterial hypertension through enhanced Gα13/p115RhoGEF/RhoA signaling (2012)
  • Author(s): Nakanishi N, Ogata T, Miyagawa K, Naito D, Taniguchi T, Ueyama T, Matsubara H
  • Organizer: American Heart Association Scientific Session 2012
  • Place of Presentation: Las Vegas, USA
• [Presentation] MURC/Cavin-4 functions as a negative regulator of caveolin-3 in the development of heart failure (2012)
  • Author(s): Naito D, Ueyama T, Kobara M, Amano K, Ogata T, Taniguchi T, Nakanishi N, Miyagawa K, Matsubara H
  • Organizer: American Heart Association Scientific Session 2012
  • Place of Presentation: Las Vegas, USA
• [Presentation] MURC/Cavin-4, a new caveolar scaffolding protein for activated ERK, regulates cardiac hypertrophy induced byα1-adrenergic agonist (2012)
  • Author(s): Ogata T, Ueyama T, Taniguchi T, Naito D, Nakanishi N, Miyagawa K, Hamaoka T, Matsubara H
  • Organizer: American Heart Association Scientific Session 2012
  • Place of Presentation: Las Vegas, USA
• [Presentation] Caveolae-related genes in heart failure and arrhythmia (2012)
  • Author(s): Ueyama T, Ogata T, Amano K, Matsubara H
  • Organizer: 第76回日本循環器学会学術集会
  • Place of Presentation: 福岡県
• [Presentation] MURC functions as a caveolar scaffold protein for Rho signaling that regulates proliferation and migration of vascular smooth muscle cells (2012)
  • Author(s): Nakanishi N, Ogata T, Miyagawa K, Naito D, Taniguchi T, Amano K, Ueyama T, Matsubara H
  • Organizer: 第76回日本循環器学会学術集会
  • Place of Presentation: 福岡県
• [Presentation] Loss of MURC targeting to caveolae causes progressive cardiac dysfunction and intraventricular conduction delay (2012)
  • Author(s): Naito D, Amano K, Ogata T, Taniguchi T, Nakanishi N, Miyagawa K, Ueyama T, Matsubara H
  • Organizer: 第76回日本循環器学会学術集会
  • Place of Presentation: 福岡県
• [Presentation] MURC/Cavin-4 is a new caveolar scaffolding protein for phosphorylated ERK and regulatesα1-adrenergic agonist-induced cardiomyocyte hypertrophy (2012)
  • Author(s): Ogata T, Ueyama T, Naito D, Taniguchi T, Nakanishi N, Miyagawa K, Amano K, Matsubara H
  • Organizer: 第49回日本臨床分子医学会学術集会
  • Place of Presentation: 京都府
• [Presentation] 筋特異的カベオラ蛋白MURCはCaveolin-1とGα13-GTPの結合を競合阻害し、Rho/ROCK pathwayを介した肺血管平滑筋細胞の増殖能・遊走能を亢進させる (2012)
  • Author(s): 中西直彦、小形岳寛、宮川浩太郎、内藤大督、谷口琢也、沢田尚久、上山知己、松原弘明
  • Organizer: 第1回日本肺循環学会学術集会
  • Place of Presentation: 東京都
• [Presentation] Impairment of MURC/Cavin-4 localization to caveolae causes progressive cardiac dysfunction and intraventricular conduction delay (2012)
  • Author(s): Naito D, Amano K, Ogata T, Taniguchi T, Nakanishi N, Miyagawa K, Ueyama T, Matsubara H
  • Organizer: 第29回国際心臓研究学会(ISHR)日本部会総会
  • Place of Presentation: 福岡県
• [Presentation] MURC/cavin-4 Functions as a Negative Regulator of Caveolin-3 in The Development of Heart Failure. (2012)
  • Author(s): Naito D, et al.
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: Los Angeles, USA
• [Presentation] MURC/Cavin-4, a New Caveolar Scaffolding Protein for Activated ERK, Regulates Cardiac Hypertrophy Induced by α1-Adrenergic Agonist. (2012)
  • Author(s): Ogata T, et al.
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: Los Angeles, USA
• [Presentation] MURC regulates proliferation of vascular smooth muscle cells through the Rho/ROCK pathway (2011)
  • Author(s): Nakanishi N, Ogata T, Miyagawa K, Naito D, Taniguchi T, Amano K, Ueyama T, Matsubara H
  • Organizer: 第75回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] MURC, muscle-restricted coiled-coil protein, is a component of the caveolin-cavin complex and regulates caveolae morphology in cardiomyocytes (2011)
  • Author(s): Naito D, Amano K, Ogata T, Taniguchi T, Nakanishi N, Miyagawa K, Hayashi YK, Morimoto T, Ueyama T, Matsubara H
  • Organizer: 第75回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] NFAT5 is essential for mesodermal and cardiomyogenic differentiation through regulating the canonical Wnt pathway (2011)
  • Author(s): Adachi A, Takahashi T, Imoto H, Nakanishi N, Kangawa H, Ueyama T, Matsubara H
  • Organizer: 第75回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] MURC/Cavin-4のRho/ROCK pathwayを介した血管平滑筋機能制御メカニズムの検討 (2011)
  • Author(s): 中西直彦,小形岳寛,宮川浩太郎,内藤大督,谷口琢也,天野克也,上山知己,松原弘明
  • Organizer: 第34回日本高血圧学会総会
  • Place of Presentation: 宇都宮
• [Presentation] MURC regulates proliferation of vascular smooth muscle cells through the Rho/ROCK pathway. (2011)
  • Author(s): Nakanishi N, Ogata T, Miyagawa K, Naito D, Taniguchi T, Amano K, Ueyama T, Matsubara H.
  • Organizer: 第75回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] MURC, muscle-restricted coiled-coil protein, is a component of the caveolin-cavin complex and regulates caveolae morphology in cardiomyocytes. (2011)
  • Author(s): Naito D, Amano K, Ogata T, Taniguchi T, Nakanishi N, Miyagawa K, Hayashi YK, Morimoto T, Ueyama T, Matsubara H.
  • Organizer: 第75回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] NFAT5 is essential for mesodermal and cardiomyogenic differentiation through regulating the canonical Wnt pathway. (2011)
  • Author(s): Adachi A, Takahashi T, Imoto H, Nakanishi N, Kangawa H, Ueyama T, Matsubara H.
  • Organizer: 第75回日本循環器学会総会
  • Place of Presentation: 横浜
• [Presentation] MURC/Cavin-4のRho/ROCK pathwayを介した血管平滑筋機能制御メカニズムの検討． (2011)
  • Author(s): 中西直彦，小形岳寛，宮川浩太郎，内藤大督，谷口琢也，天野克也，上山知己，松原弘明．
  • Organizer: 第34回日本高血圧学会総会
  • Place of Presentation: 宇都宮
• [Remarks] 循環器・腎臓内科ホームページ
  • URL: http://www.f.kpu-m.ac.jp/k/med2/index.html