The role of leucine-rich alpha2 glycoprotein in cardiac remodeling

• Project/Area Number: 15K15052
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Osaka University
• Principal Investigator: Nakayama Hiroyuki 大阪大学, 薬学研究科, 准教授 (40581062)
• Co-Investigator(Kenkyū-buntansha): 藤尾 慈 大阪大学, 薬学研究科, 教授 (20359839) ; 仲 哲治 国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 免疫シグナルプロジェクト, 招へいプロジェクトリーダー (30303936)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 心筋梗塞 / リモデリング / 血管新生 / マクロファージ / 炎症 / 心筋梗塞後リモデリング / LRG / 心筋リモデリング

Outline of Final Research Achievements

Leucine-rich α2-glycoprotein (LRG) is considered as a biomarker of chronic inflammatory diseases. In this study, we addressed functional roles of LRG in cardiac remodeling after myocardial infarction (MI). The expressions of LRG were upregulated in post-infarct myocardium and observed in heart-infiltrated myeloid cells. To elucidate functional roles of LRG in cardiac remodeling, we generated MI in wild-type (WT) and LRG null (LRG-/-) mice and found that LRG gene ablation aggravated myocardial fibrosis with cardiac dysfunction after MI with decreased capillary density at border zone. Consistently, the expression of apelin receptor was reduced in LRG-/- mice, implying that the impaired angiogenic activity is associated with adverse cardiac remodeling in LRG-/- mice. Moreover, LRG gene ablation suppressed the activation of smad1/5/8, a pro-angiogenic signaling pathway. Thus, our data indicate significant roles of myeloid cells in angiogenesis as well as its molecular mechanism.

Research Products

• [Journal Article] Phospholamban inhibition by a single dose administration of locked nucleic acid antisense oligonucleotide improves cardiac contractility in pressure overload-induced systolic dysfunction in mice. (2017)
  • Author(s): Morihara, H., Yamamoto, T., Oiwa, H., Tonegawa, K., Tsuchiyama, D., Kawakatsu, I., Obana, M., Maeda, M., Mohri, T., Obika, S., Fujio, Y., Nakayama, H.
  • Journal Title: J. Cardiovasc. Pharmacol. Ther. Volume: 印刷中 Issue: 3 Pages: 273-282
  • DOI: 10.1177/1074248416676392
  • Peer Reviewed / Open Access
• [Journal Article] Myeloid cell-derived LRG attenuates adverse cardiac remodeling after myocardial infarction. (2016)
  • Author(s): Kumagai, S., Nakayama, H., Fujiomoto, M., Honda, H., Serada, S., Ishibashi-Ueda, H., Kasai, A., Obana, M., Sawa, Y., Fujio, Y., Naka, T.
  • Journal Title: Cardiovasc. Res. Volume: 109 Issue: 2 Pages: 272-282
  • DOI: 10.1093/cvr/cvv273
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Persistent increases in Ca(2+) influx through Cav1.2 shortens action potential and causes Ca(2+) overload-induced afterdepolarizations and arrhythmias. (2016)
  • Author(s): Zhang X, Ai X, Nakayama H, Chen B, Harris DM, Tang M, Xie Y, Szeto C, Li Y, Li Y, Zhang H, Eckhart AD, Koch WJ, Molkentin JD, Chen X.
  • Journal Title: Basic Res Cardiol Volume: 111 Issue: 1 Pages: 4-4
  • DOI: 10.1007/s00395-015-0523-4
  • Peer Reviewed / Open Access
• [Journal Article] Moesin is activated in cardiomyocytes in experimental autoimmune myocarditis and mediates cytoskeletal reorganization with protrusion formation (2016)
  • Author(s): Akimitsu Miyawaki, Yusuke Mitsuhara, Aya Orimoto, Yusuke Nakayasu, Shin-ichi Tsunoda, Masanori Obana, Makiko Maeda, Hiroyuki Nakayama, Yasuo Yoshioka, Yasuo Tsutsumi, Yasushi Fujio
  • Journal Title: The American Journal of Physiology-Heart and Circulatory Physiology Volume: 311 Issue: 2 Pages: 476-486
  • DOI: 10.1152/ajpheart.00180.2016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Macromolecular Degradation Systems and Cardiovascular Aging. (2016)
  • Author(s): Nakayama H, Nishida K, Otsu K.
  • Journal Title: Circ Res Volume: 118 Issue: 10 Pages: 1577-92
  • DOI: 10.1161/circresaha.115.307495
  • Peer Reviewed / Open Access
• [Journal Article] Cardiac specific ablation of STAT3 gene in subacute phase of myocardial infarction exacerbated cardiac remodeling. (2015)
  • Author(s): Enomoto, D., Obana, M., Miyawaki, A., Maeda, M., Nakayama, H., Fujio, Y.
  • Journal Title: Am. J. Physiol. Heart Circ. Physiol. Volume: 3０９ Issue: 3 Pages: H471-H480
  • DOI: 10.1152/ajpheart.00730.2014
  • Peer Reviewed / Open Access
• [Presentation] Fibroblast-specific beta2 adrenergic receptor signaling regulates cardiac hypertrophy in mice. (2016)
  • Author(s): Kota Tonegawa, Shota Tanaka, Misato Takahashi, Shota Fuchigami, Masanori Obana, Makiko Maeda, Yasushi Sakata, Yasushi Fujio, Hiroyuki Nakayama
  • Organizer: American Heart Association 2016 Scientific Sessions
  • Place of Presentation: New Orleans
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Myeloid cell-specific Runx2 deficiency exacerbates adverse cardiac remodeling after myocardial infarction (2016)
  • Author(s): Moe Ashizuka, Shohei Kumagai, Emiko Yanase, Masanori Obana, Makiko Maeda, Yasushi Sakata, Hiroyuki Nakayama, Yasushi Fujio
  • Organizer: American Heart Association 2016 Scientific Sessions
  • Place of Presentation: New Orleans
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Adult Mammalian Hearts Restore Intrinsic Regenerative Capacity through Signal Transducer and Activator of Transcription 3 in the Resolution Phase of Myocarditis (2016)
  • Author(s): Akimitsu Miyawaki, Masanori Obana, Yusuke Mitsuhara, Aya Orimoto, Yusuke Nakayasu, Tomomi Yamashita, So-ichiro Fukada, Makiko Maeda, Yasushi Sakata, Hiroyuki Nakayama, Yasushi Fujio.
  • Organizer: American Heart Association 2016 Scientific Sessions
  • Place of Presentation: New Orleans
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Heterozygous ablation of RORγt gene deteriorates adverse cardiac remodeling after myocardial infarction (2016)
  • Author(s): Daichi Enomoto, Masanori Obana, Kotaro Matsumoto, Yasushi Sakata, Makiko Maeda, Hiroyuki Nakayama, Yasushi Fujio
  • Organizer: American Heart Association 2016 Scientific Sessions
  • Place of Presentation: New Orleans
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Cardiac STAT3 Activation in Subacute Phase of Myocardial Infarction was Required for the Suppression of Adverse Cardiac Remodeling. (2015)
  • Author(s): 1.Enomoto D, Obana M, Miyawaki A, Mohri T, Maeda M, Sakata Y, Nakayama H, Fujio Y.
  • Organizer: American Heart Association Scientific Session 2015
  • Place of Presentation: 米国オーランド
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Blockade of NKG2D / NKG2D Ligands Interaction Attenuated Cardiac Remodeling After Myocardial Infarction. (2015)
  • Author(s): 2.Matsumoto K, Obana M, Hashizume R, Yokoyama Y, Miyagawa S, Mohri T, Maeda M, Nakayama H, Sawa Y, Fujio Y.
  • Organizer: American Heart Association Scientific Session 2015
  • Place of Presentation: 米国オーランド
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Adrenergic Receptors β2 and β3 Transduce Differential Signals in Cardiac Fibroblasts. (2015)
  • Author(s): 3.Tonegawa K, Nakayama H, Igarashi H, Matsunami S, Hayamizu N, Obana M, Maeda M, Fujio Y.
  • Organizer: American Heart Association Scientific Session 2015
  • Place of Presentation: 米国オーランド
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Myeloid Cell Derived Leucine Rich α2 Glycoprotein Attenuates Adverse Cardiac Remodeling After Myocardial Infarction. (2015)
  • Author(s): 4.Kumagai S, Nakayama H, Fujimoto M, Honda H, Serada S, Kasai A, Obana M, Sakata Y, Sawa Y, Naka T, Fujio Y
  • Organizer: American Heart Association Scientific Session 2015
  • Place of Presentation: 米国オーランド
  • Year and Date: 2015-11-07
  • Int'l Joint Research