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Original Article

Novel Role for the Immunoproteasome Subunit PSMB10 in Angiotensin II–Induced Atrial Fibrillation in MiceNovelty and Significance

Jing Li, Shuai Wang, Jie Bai, Xiao-Lei Yang, Yun-Long Zhang, Yi-Lin Che, Hui-Hua Li, Yan-Zong Yang
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https://doi.org/10.1161/HYPERTENSIONAHA.117.10390
Hypertension. 2018;71:866-876
Originally published March 5, 2018
Jing Li
From the Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China (J.L., X.-L.Y., Y.-L.Z., Y.-Z.Y., H.-H.L.); Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, China (J.B., H.-H.L.); and Department of Ophthalmology (S.W.) and Department of Radiotherapy Oncology (Y.-L.C.), The Second Affiliated Hospital of Dalian Medical University, China.
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Shuai Wang
From the Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China (J.L., X.-L.Y., Y.-L.Z., Y.-Z.Y., H.-H.L.); Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, China (J.B., H.-H.L.); and Department of Ophthalmology (S.W.) and Department of Radiotherapy Oncology (Y.-L.C.), The Second Affiliated Hospital of Dalian Medical University, China.
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Jie Bai
From the Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China (J.L., X.-L.Y., Y.-L.Z., Y.-Z.Y., H.-H.L.); Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, China (J.B., H.-H.L.); and Department of Ophthalmology (S.W.) and Department of Radiotherapy Oncology (Y.-L.C.), The Second Affiliated Hospital of Dalian Medical University, China.
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Xiao-Lei Yang
From the Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China (J.L., X.-L.Y., Y.-L.Z., Y.-Z.Y., H.-H.L.); Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, China (J.B., H.-H.L.); and Department of Ophthalmology (S.W.) and Department of Radiotherapy Oncology (Y.-L.C.), The Second Affiliated Hospital of Dalian Medical University, China.
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Yun-Long Zhang
From the Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China (J.L., X.-L.Y., Y.-L.Z., Y.-Z.Y., H.-H.L.); Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, China (J.B., H.-H.L.); and Department of Ophthalmology (S.W.) and Department of Radiotherapy Oncology (Y.-L.C.), The Second Affiliated Hospital of Dalian Medical University, China.
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Yi-Lin Che
From the Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China (J.L., X.-L.Y., Y.-L.Z., Y.-Z.Y., H.-H.L.); Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, China (J.B., H.-H.L.); and Department of Ophthalmology (S.W.) and Department of Radiotherapy Oncology (Y.-L.C.), The Second Affiliated Hospital of Dalian Medical University, China.
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Hui-Hua Li
From the Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China (J.L., X.-L.Y., Y.-L.Z., Y.-Z.Y., H.-H.L.); Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, China (J.B., H.-H.L.); and Department of Ophthalmology (S.W.) and Department of Radiotherapy Oncology (Y.-L.C.), The Second Affiliated Hospital of Dalian Medical University, China.
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Yan-Zong Yang
From the Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China (J.L., X.-L.Y., Y.-L.Z., Y.-Z.Y., H.-H.L.); Department of Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, China (J.B., H.-H.L.); and Department of Ophthalmology (S.W.) and Department of Radiotherapy Oncology (Y.-L.C.), The Second Affiliated Hospital of Dalian Medical University, China.
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Abstract

Angiotensin II (Ang II) and inflammation are associated with pathogenesis of atrial fibrillation (AF), but the underlying molecular mechanisms of these events remain unknown. The immunoproteasome has emerged as a critical regulator of inflammatory responses. Here, we investigated its role in Ang II–induced AF in immunosubunit PSMB10 (also known as β2i or LMP10) knockout (KO) mice. AF was induced by Ang II infusion (2000 ng/min per kg). PSMB10 expression and trypsin-like activity were increased in atrial tissues and serum from Ang II–treated mice or serum from patients with AF. Moreover, Ang II–infused wild-type (WT) mice had a higher AF and increased atrial fibrosis, reactive oxygen species production, and inflammation compared with saline-treated WT animals. These effects were attenuated in PSMB10 KO mice but were aggravated in recombinant adeno-associated virus serotype 9-PSMB10–treated mice. Administration of IKKβ-specific inhibitor IMD 0354 reduced Ang II–induced AF, reactive oxygen species production, inflammation, and NF-kB (nuclear factor-kB) activation. Mechanistically, Ang II infusion upregulated PSMB10 expression to promote PTEN (phosphatase and tensin homolog deleted on chromosome ten) degradation and AKT1 activation, which not only activated TGF-β–Smad2/3 signaling leading to cardiac fibrosis but also induced IKKβ activation and ubiquitin-mediated degradation of IkBα ultimately resulting in activation of NF-kB target genes (IL [interleukin]-1β, IL-6, NOX [NADPH oxidase] 2, NOX4, and CX43 [connexin 43]). Overall, our study identifies immunosubunit PSMB10 as a novel regulator that contributes to Ang II–induced AF and suggests that inhibition of PSMB10 may represent a potential therapeutic target for treating hypertensive AF.

  • angiotensin II
  • animals
  • atrial fibrillation
  • immunoproteasome
  • inflammation
  • PSMB10
  • Received September 26, 2017.
  • Revision received October 14, 2017.
  • Accepted February 11, 2018.
  • © 2018 American Heart Association, Inc.

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    Novel Role for the Immunoproteasome Subunit PSMB10 in Angiotensin II–Induced Atrial Fibrillation in MiceNovelty and Significance
    Jing Li, Shuai Wang, Jie Bai, Xiao-Lei Yang, Yun-Long Zhang, Yi-Lin Che, Hui-Hua Li and Yan-Zong Yang
    Hypertension. 2018;71:866-876, originally published March 5, 2018
    https://doi.org/10.1161/HYPERTENSIONAHA.117.10390

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    Novel Role for the Immunoproteasome Subunit PSMB10 in Angiotensin II–Induced Atrial Fibrillation in MiceNovelty and Significance
    Jing Li, Shuai Wang, Jie Bai, Xiao-Lei Yang, Yun-Long Zhang, Yi-Lin Che, Hui-Hua Li and Yan-Zong Yang
    Hypertension. 2018;71:866-876, originally published March 5, 2018
    https://doi.org/10.1161/HYPERTENSIONAHA.117.10390
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