Establishment of a novel therapeutic strategy for atherosclerosis utilizing a focal adhesion adaptor molecule

• Project/Area Number: 26461149
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Showa University
• Principal Investigator: Kaneyama Shuri 昭和大学, 医学部, 准教授 (10338535)
• Co-Investigator(Kenkyū-buntansha): 宮崎 章 昭和大学, 医学部, 教授 (70253721)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: HIc-5 / 細胞接着斑 / 動脈硬化性疾患 / Hic-5 / 阻害ペプチド / 制御化合物探索

Outline of Final Research Achievements

Hydrogen peroxide-inducible clone-5 (Hic-5) is a focal adhesion adaptor protein, which is involved in vascular disorders such as atherosclerosis and aneurysms. To evaluate the therapeutic potential of Hic-5 in vascular disorders, Hic-5 siRNA was intravenously injected through the tail vein of the HCD-fed or AngII treated apoE deficient mice. Hic-5 knockdown significantly suppressed the formation of atherosclerotic and aneurysmal lesions. Moreover, we report the structure-based design of new potent peptides with Hic-5 inhibitory efficiency. The peptides are developed by rational design, based on structural and physicochemical properties. In vitro analysis shows that some of the peptides possess a significant inhibitory effect against Hic-5.

Research Products

• [Int'l Joint Research] KAIST(韓国)
• [Int'l Joint Research] Massachusetts General Hospital(米国)
• [Int'l Joint Research] Institut Albert Bonniot(France)
• [Int'l Joint Research] Institut Albert Bonniot(France)
• [Journal Article] Functional Heterogeneity of Nadph Oxidases in Atherosclerotic and Aneurysmal Diseases (2017)
  • Author(s): Kigawa Y, Miyazaki T, Lei XF, Kim-Kaneyama JR, Miyazaki A.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 24 Issue: 1 Pages: 1-13
  • DOI: 10.5551/jat.33431
  • NAID: 130005188266
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access
• [Journal Article] The LIM protein complex establishes a retinal circuitry of visual adaptation by regulating Pax6 α-enhancer activity. (2017)
  • Author(s): Kim Y, Lim S, Ha T, Song YH, Sohn YI, Park DJ, Paik SS, Kim-Kaneyama JR, Song MR, Leung A, Levine EM, Kim IB, Goo YS, Lee SH, Kang KH, Kim JW.
  • Journal Title: Elife. Volume: 6
  • DOI: 10.7554/elife.21303
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The pathophysiological role of oxidized cholesterols in epicardial fat accumulation and cardiac dysfunction: a study in swine fed a high caloric diet with an inhibitor of intestinal cholesterol absorption, ezetimibe. (2016)
  • Author(s): Shimabukuro M, Okawa C, Yamada H, Yanagi S, Uematsu E, Sugasawa N, Kurobe H, Hirata Y, Kim-Kaneyama JR, Lei XF, Takao S, Tanaka Y, Fukuda D, Yagi S, Soeki T, Kitagawa T, Masuzaki H, Sato M, Sata M.
  • Journal Title: J Nutr Biochem. Volume: 35 Pages: 66-73
  • DOI: 10.1016/j.jnutbio.2016.05.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicing. (2016)
  • Author(s): Miyazaki T, Tonami K, Hata S, Aiuchi T, Ohnishi K, Lei XF, Kim-Kaneyama JR, Takeya M, Itabe H, Sorimachi H, Kurihara H, Miyazaki A
  • Journal Title: J Clin Invest Volume: 126 Issue: 9 Pages: 3417-3432
  • DOI: 10.1172/jci85880
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hic-5 deficiency attenuates the activation of hepatic stellate cells and liver fibrosis through upregulation of Smad7 in mice (2016)
  • Author(s): Xiao-Feng Lei, Wenguang Fu, Joo-ri Kim-Kaneyama, Tomokatsu Omoto, Takuro Miyazaki, Bo Li, Akira Miyazaki
  • Journal Title: Journal of Hepatology Volume: 64 Issue: 1 Pages: 110-117
  • DOI: 10.1016/j.jhep.2015.08.026
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Comparison of mouse and human ankles and establishment of mouse ankle osteoarthritis models by surgically-induced instability (2016)
  • Author(s): Chang SH, Yasui T, Taketomi S, Matsumoto T, Kim-Kaneyama JR, Omiya T, Hosaka Y, Inui H, Omata Y, Yamagami R, Mori D, Yano F, Chung U, Tanaka S, Saito T.
  • Journal Title: Osteoarthritis Cartilage Volume: 24 Issue: 4 Pages: 688-697
  • DOI: 10.1016/j.joca.2015.11.008
  • Peer Reviewed
• [Journal Article] Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue (2016)
  • Author(s): Nishimoto S, Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Murata C, Kim-Kaneyama JR, Sato F, Bando M, Yagi S, Soeki T, Hayashi T, Imoto I, Sakaue H, Shimabukuro M, Sata M.
  • Journal Title: Sci Adv. Volume: 2(3) Issue: 3
  • DOI: 10.1126/sciadv.1501332
  • Peer Reviewed / Open Access
• [Journal Article] Paxillin-JAK1 and Hic-5-IQGAP1 pathways couple the acto-adhesive and ECM (2016)
  • Author(s): Petropoulos C, Oddou C, Emadali A, Hiriart-Bryant E, Boyault C, Faurobert E, Vande S, Kim-Kaneyama JR, Alexandra Kraut, Coute Y, Block M, Albiges-Rizo C and Destaing O.
  • Journal Title: Journal of Cell Biology Volume: in press
  • Peer Reviewed
• [Journal Article] Role of HIC-5 in the formation of microvilli-like structures and the monocyte-endotherial interaction that accelerates atherosclerosis (2015)
  • Author(s): Shigeko Arita-Okubo, et al
  • Journal Title: Cardiovasc Res Volume: 105 Issue: 3 Pages: 361-371
  • DOI: 10.1093/cvr/cvv003
  • Peer Reviewed / Open Access
• [Journal Article] Calpastatin counteracts pathological angiogenesis by inhibiting suppressor of cytokine signaling 3 degradation in vascular endothelial cells. (2015)
  • Author(s): Miyazaki, T., Taketomi, Y., Saito, Y., Hosono, T., Lei, X.F., Kim-Kaneyama, J.R., Arata, S., Takahashi, H., Murakami, M., and Miyazaki, A.
  • Journal Title: Circ. Res. Volume: 116 Issue: 7 Pages: 1170-1181
  • DOI: 10.1161/circresaha.116.305363
  • Peer Reviewed / Open Access
• [Journal Article] Hydrogen peroxide-inducible clone-5 regulates mesangial cell proliferation in proliferative glomerulonephritis in mice. (2015)
  • Author(s): Jamba A, Kondo S, Urushihara M, Nagai T, Kim-Kaneyama JR, Miyazaki A, Kagami S.
  • Journal Title: PLoS One. Volume: 10(4) Issue: 4 Pages: e0122773-e0122773
  • DOI: 10.1371/journal.pone.0122773
  • Peer Reviewed / Open Access
• [Journal Article] NADPH oxidase deficiency exacerbates angiotensin II-induced abdominal aortic aneurysms in mice. (2014)
  • Author(s): Kigawa Y, Miyazaki T, Lei XF, Nakamachi T, Oguchi T, Kim-Kaneyama JR, Taniyama M, Tsunawaki S, Shioda S, Miyazaki A
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 34 Issue: 11 Pages: 2413-2420
  • DOI: 10.1161/atvbaha.114.303086
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 肝線維化におけるTGF-β関連遺伝子Hic-5の機能解析 (2016)
  • Author(s): 雷 小峰、金山 朱里、宮崎 章
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張, 千葉
  • Year and Date: 2016-05-19
• [Presentation] Roles of hydrogen peroxide inducible clone 5 in pathogenesis of thoracic aortic aneurysm in Marfan syndrome (2016)
  • Author(s): Xiao-Feng Lei, Joo-ri Kim-Kaneyama, Takuro Miyazaki, Akira Miyazaki
  • Organizer: 19th International Vascular Biology Meeting
  • Place of Presentation: Boston, United States
  • Int'l Joint Research
• [Presentation] カルパイン-６はmRNAの成熟不全を介してマクロファージLDL取込みを促進する (2016)
  • Author(s): 宮﨑 拓郎, 雷 小峰、 金山 朱里、 宮崎 章
  • Organizer: 第58回日本脂質生化学会
  • Place of Presentation: 秋田
• [Presentation] Hic-5 deficiency attenuates the activation of hepatic stellate cells and liver fibrosis through upregulation of Smad7 in mice (2015)
  • Author(s): Xiao-Feng Lei, Wenguang Fu, JR Kim-Kaneyama, Akira Miyazaki.
  • Organizer: 18th INTERNATIONAL SYMPOSIUM ON CELLS OF THE HEPATIC SINUSOID
  • Place of Presentation: Asilomar, California
  • Year and Date: 2015-11-11
  • Int'l Joint Research
• [Presentation] 肝線維化におけるTGF-beta 誘導分子Hic-5の機能解析 (2015)
  • Author(s): 雷 小峰、付 文広、金山 朱里、大久保 茂子、宮崎 拓郎、宮崎 章
  • Organizer: 日本結合組織学会学術大会
  • Place of Presentation: 東京都港区
  • Year and Date: 2015-05-15 – 2015-05-16
• [Remarks] 昭和大学医学部生化学
  • URL: http://www10.showa-u.ac.jp/~biochem/Biochem/Biochem_top.html