Mechanical role of tyrosine kinase PYK2 in cardiovascular stress response and therapeutic regulation of the kinase activity

2010 Fiscal Year Final Research Report

• Project/Area Number: 20590884
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: OKIGAKI Mituhiko 京都府立医科大学, 医学研究科, 准教授 (10333197)
• Project Period (FY): 2008 – 2010
• Keywords: ストレス / PYK2 / チロシンキナーゼ / 活性酸素 / 血管生物学

Research Abstract

We have clarified that various cardiovascular stress activates tyrosine kinase PYK2.The activated PYK2 subsequently produce Reactive Oxygen Species(ROS) production and the ROS promotes cardiovascular inflammation, leading to many cardiovascular disease such as atherosclerosis, cardiovascular remodeling after myocardial ischemia and pressure-overload by aortic banding, neointimal hypertrophy after endothelial damages. In this study, we studied whether inhibition of PYK2 in vivo may attenuate the cardiovascular diseases in mice model. We intravenously introduced PYK2-shRNA into mice to knockdown PYK2 in vivo. Expression levels of PYK2 in heart, aorta and kidney decreased less than 30% of the control. Then, 14 days after introducing shRNA for PYK2, the mice was conducted the cardiovascular injury model described above. We observed that endothelial injury by guide wire, hypercholesterolemia under Apo-E deficiency, medial hypertrophy after Angiotensin-II infusion, myocardial hypertrophy after aortic banding was markedly attenuated. Thus, PYK2 is novel and potential therapeutic target of various cardiovascular diseases.

Research Products

• [Journal Article] 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/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 Pages: 1084-92
• [Journal Article] Endothelial FGF receptor signaling accelerates atherosclerosis (2011)
  • Author(s): Che J, Okigaki M, Takahashi T, Katsume A, Adachi Y, Yamaguchi S, Matsunaga S, Takeda M, Matsui A, Kishita E, Ikeda K, Yamada H, Matsubara H
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: 300 Pages: 154-61
• [Journal Article] Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2+channel to maintain endothelial integrity (2010)
  • Author(s): Kusaba T, Okigaki M, Matui A, Murakami M, Ishikawa K, Kimura T, Sonomura K, Adachi Y, Shibuya M, Shirayama T, Tanda S, Hatta T, Sasaki S, Mori Y, Matsubara H
  • Journal Title: Proc Natl Acad Sci U S A Volume: 107 Pages: 19308-13
• [Presentation] Aldosterone promotes vascular inflammation mediated by trans-activation of Caveolin/Angiotensin-II-Receptor-Type-1/tyrosine kinase PYK2 pathway (2011)
  • Author(s): Yamaguchi S, Matui A, Okigaki M, Fukai K, Matsubara H
  • Organizer: American Heart Association Scientific Sessions
  • Place of Presentation: Orland, USA
  • Year and Date: 20111112-16
• [Presentation] Non-genomic action of Aldosterone in VSMC requires translocation of Mineralocorticoid Receptor to the Caveolae in the plasma-membrane and sub-sequent trans-activation of AngiotensinII Type1 Receptor and its downstream tyrosine kinase PYK2/ROS/MAPK pathway (2010)
  • Author(s): Yamaguchi S, Matui A, Okigaki M, Matsubara H
  • Organizer: American Heart Association Scientific Sessions
  • Place of Presentation: Chicago, USA
  • Year and Date: 20101113-17
• [Presentation] Ca2+/Redox-Sensitive Tyrosine Kinase PYK2 Promotes Atherogenesis Through OxLDL/ROS/p21-Dependent Premature Senescence in Endothelium (2009)
  • Author(s): Katsume A, Okigaki M, Matsui A, Jisan C, Yamaguchi S, Yamada H, Matsubara H
  • Organizer: American Heart Association Scientific Sessions
  • Place of Presentation: Orland, USA
  • Year and Date: 20091114-18
• [Presentation] Calcium/Redox Sensitive Tyrosine Kinase Pyk2 Aggravates Myocardial Ishemia by Promoting Inflammatory Reactions and Cell Apoptosis (2008)
  • Author(s): Kishita E, Honsho S, Yamaguchi S, Katsume A, Matsui A, Matsunaga S, Okigaki M, Matsubara H
  • Organizer: American Heart Association Scientific Sessions
  • Place of Presentation: New Orleans, USA
  • Year and Date: 20081108-12