Regulation of macrophage foam cell formation and atherosclerosis by tissue-specific calpains

• Project/Area Number: 26461368
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Showa University
• Principal Investigator: MIYAZAKI AKIRA 昭和大学, 医学部, 教授 (70253721)
• Research Collaborator: MIYAZAKI Takuro 昭和大学, 医学部生化学講座, 講師 (80398693)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: カルパイン / ピノサイトーシス / マクロファージ / 動脈硬化 / カルパイン６ / CWC22

Outline of Final Research Achievements

Calpain-6, a member of calpain superfamily that has no proteolytic activity, was shown to be highly expressed in inflammatory macrophages and interact in the cytoplasm with CWC22, a factor that promotes nuclear translocation of exon-junction complexes, thereby interfering with nuclear translocation of CWC22. Association of CPNA6 with CWC22 led to suppression of mRNA splicing of various genes including Rac1 and acceleration of LDL pinocytosis by macrophages and subsequent development of atherosclerosis in mice.

Research Products

• [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] 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] 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] 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] 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
• [Journal Article] Identification of hydrogen peroxide-inducible clone 5 as a novel scaffold for the mitogen-activated protein kinase kinase 4/p54 c-Jun N-terminal kinase pathway in the development of abdominal aortic aneurysms (2014)
  • Author(s): Lei XF, Kim-Kaneyama JR, Arita-Okubo S, Offermanns S, Itabe H, Miyazaki T, Miyazaki A
  • Journal Title: J Am Heart Assoc Volume: 3 Issue: 3
  • DOI: 10.1161/jaha.113.000747
  • Peer Reviewed / Open Access
• [Presentation] Disturbance of pre-mRNA splicing by calpain-6 aggravates macrophage cholesterol deposition in atherosclerotic lesions. (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.
  • Organizer: 第24回日本血管生物医学会学術集会
  • Place of Presentation: 長崎ブリックホール
  • Year and Date: 2016-12-09
  • Invited
• [Presentation] Calpain-6 potentiates pro-atherogenic pinocytosis in macrophages. (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.
  • Organizer: 19th International vascular biology meeting
  • Place of Presentation: Sheraton Boston Hotel, Boston, 米国
  • Year and Date: 2016-11-01
  • 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): 宮崎 拓郎, 雷 小峰, 金山 朱里, 宮崎 章
  • Organizer: 第58回日本脂質生化学会大会
  • Place of Presentation: 秋田市にぎわい交流館AU
  • Year and Date: 2016-06-09
• [Presentation] カルパインシステムによるJAK/STAT経路依存的な病的血管新生の制御 (2015)
  • Author(s): 宮崎 拓郎, 武富 芳隆, 雷 小峰, 金山 朱里, 村上 誠, 宮崎 章
  • Organizer: BMB2015（日本分子生物学会 日本生化学会合同大会）
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-02
• [Presentation] カルパインシステムによるJAK/STAT経路依存的な病的血管新生の制御 (2015)
  • Author(s): 宮崎 拓郎, 雷 小峰, 金山 朱里, 宮崎 章
  • Organizer: 第47回日本動脈硬化学会学術集会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2015-07-10
• [Presentation] カルパイン－6によるマクロファージ飲作用・LDL取込ならびに動脈硬化病変の制御 (2015)
  • Author(s): 宮崎 拓郎, 雷 小峰, 金山 朱里, 宮崎 章
  • Organizer: 第57回日本脂質生化学会大会
  • Place of Presentation: 一橋大学一橋講堂
  • Year and Date: 2015-05-29
• [Presentation] Calpastatin counteracts pathological angiogenesis by inhibiting suppressor of cytokine signaling 3 degradation in vascular endothelial cells (2015)
  • Author(s): Takuro Miyazaki, Yoshitaka Taketomi, Yuta Saito, Tomohiko Hosono, Xiao-Feng Lei, Joo-ri Kim-Kaneyama, Satoru Arata, Haruo Takahashi, Makoto Murakami, Akira Miyazaki
  • Organizer: XVII International Symposium on Atherosclerosis
  • Place of Presentation: アムステルダム
  • Year and Date: 2015-05-24
  • Int'l Joint Research
• [Presentation] Down-regulation of calpastatin in vascular endothelial cells confers immature and inflammatory properties to pathological neovessels (2014)
  • Author(s): 宮崎拓郎, 宮崎 章
  • Organizer: 第46回日本動脈硬化学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-07-10 – 2014-07-11
• [Presentation] NADPH oxidase 2 deficiency exacerbates angiotensin II-induced abdominal aortic aneurysms in mice through over-activation of inflammatory macrophages (2014)
  • Author(s): 黄川恵慈, 宮崎拓郎, 宮崎 章
  • Organizer: 第46回日本動脈硬化学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-07-10 – 2014-07-11
• [Presentation] VEGF-induced down-regulation of calpastatin in vascular endothelial cells confers destabilized and pro-inflammatory properties to pathological neovessels (2014)
  • Author(s): Miyazaki T, Taketomi Y, Hosono T, Lei XF, Kim-Kaneyama JR, Arata S, Murakami M, Miyazaki A
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: 京都
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] Identification of Hic-5 as a novel scaffold for the MKK4/JNK2 pathway in the development of abdominal aortic aneurysms (2014)
  • Author(s): Lei XF, Kim-Kaneyama JR, Arita S, Offermanns S, Miyazaki T, Miyazaki A
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: 京都
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] Identification of Hic-5 as a novel regulatory factor for integrin αIIbβ3 activation and platelet aggregation in mice (2014)
  • Author(s): Kim-Kaneyama JR, Miyauchi A, Lei XF, Arita S, Eto K, Miyazaki T, Miyazaki A
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: 京都
  • Year and Date: 2014-04-11 – 2014-04-17