A molecular link between metabolic syndrome and energy metabolism in the heart

• Project/Area Number: 23659423
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Circulatory organs internal medicine
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: MATSUBARA Hiroaki 京都府立医科大学, 大学院・医学研究科, 教授 (10239072)
• Co-Investigator(Kenkyū-buntansha): IKEDA Koji 京都府立医科大学, 医学研究科 (90423871)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 分子心臓病態学 / 心筋細胞死

Research Abstract

We have identified a novel gene, termed ARIA. ARIA is abundantly expressed in endothelial cells to regulate endothelial angiogenic functions. ARIA interacts with PTEN, a phosphatase that antagonizes PI3K signaling. Since ARIA is a membrane protein, interaction with ARIA leads to the increased membrane-association of PTEN. This increased membrane-association of PTEN causes enhanced inhibition of PI3K signaling that potently regulates cellular apoptosis. Here we found that ARIA is expressed in cardiomyocyte as well, and it regulates cardiac functions. ARIA regulates PI3K/Akt signaling in the heart, and loss of ARIA enhanced cardiac PI3K/Akt signals, leading to the resistance to cardiomyocyte apoptosis and to the stress-induced cardiomyopathy. As PI3K/Akt is a major signaling pathway for insulin, and ARIA potentially modulates the progression of obesity through a modification of adipose tissue angiogenesis, ARIA might provide a novel link between metabolic syndrome and cardiac functions.

Research Products

• [Journal Article] 2. p53-TIGAR axis attenuates mitophagy to exacerbate cardiac damage after ischemia. (2012)
  • Author(s): Hoshiono A, Matoba S, Iwai-Kanai E, Nakamura H, Kimata M, Nakaoka M, Katamura M, Okawa Y, Ariyoshi M, Mita Y, Ikeda K, Ueyama T, Okigaki M, Matsubara H.
  • Journal Title: J Mol Cell Cardiool. Volume: 52 Pages: 175-184
  • Peer Reviewed
• [Journal Article] 1. p53 promotes cardiac dysfunction in diabetic mellitus due to excessive mitochondrial respiration-mediated ROS generation and lipid accumulation. (2012)
  • Author(s): Nakamura H, Matoba S, Iwai-Kanai E, Kimata M Hoshino A, Nakaoka M, Katamura M, Okawa Y, Ariyoshi M, Mita Y, Ikeda K, Okigaki M, Adachi S, Tanaka H, Takamatsu T, Matsubara H.
  • Journal Title: Circ Heart Fail. Volume: 5 Pages: 106-15
  • Peer Reviewed
• [Journal Article] 5. Loss of Bcl-2 during the senescence exacerbates the impaired angiogenic functions in endothelial vells by deteriorating the mitiochondrial redox state. (2011)
  • Author(s): Uraoka M, Ikeda K, Kurimoto-Nakano R, Koide M, Akakabe Y, Kitamura Y, Ueyama T, Matoba S, Yamada H, Okigaki M, Matsubara H.
  • Journal Title: Hypertension Volume: 58 Pages: 256-163
  • Peer Reviewed
• [Journal Article] 4. Apoptosis regulator through modulating IAP expression (ARIA) controls PI3K/Akt pathway in endothelial and endothelial progenitor cells. (2011)
  • Author(s): Koide M, Ikeda K, Akakabe Y, Kitamura Y, Ueyama T, Matoba S, Yamada H, Okigaki M, Matsubara H.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 108 Pages: 9472-9477
  • Peer Reviewed
• [Journal Article] 3. Early inflammatory reactions in atherosclerosis are induced by proline-rich tyrosine kinase/reactive oxygen species-mediated release of tumor necrosis factor-alpha and subsequent activation of the p21Cip1/Tts-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 Pages: 1084-1092
  • Peer Reviewed