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Triad3A-Mediated K48-Linked ubiquitination and degradation of TLR9 impairs mitochondrial bioenergetics and exacerbates diabetic cardiomyopathy.

التفاصيل البيبلوغرافية
العنوان: Triad3A-Mediated K48-Linked ubiquitination and degradation of TLR9 impairs mitochondrial bioenergetics and exacerbates diabetic cardiomyopathy.
المؤلفون: Kong C; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China., Guo Z; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China., Liu F; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China., Tang N; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China., Wang M; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China., Yang D; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China., Li C; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China., Yang Z; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China., Ma Y; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China., Wang P; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China., Tang Q; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, PR China. Electronic address: qztang@whu.edu.cn.
المصدر: Journal of advanced research [J Adv Res] 2024 Jul; Vol. 61, pp. 65-81. Date of Electronic Publication: 2023 Aug 23.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Cairo University, production and hosting by Elsevier B. V Country of Publication: Egypt NLM ID: 101546952 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2090-1224 (Electronic) Linking ISSN: 20901224 NLM ISO Abbreviation: J Adv Res Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [Giza, Egypt] : Cairo University, production and hosting by Elsevier B. V.
مواضيع طبية MeSH: Diabetic Cardiomyopathies*/metabolism , Ubiquitination* , Energy Metabolism* , Toll-Like Receptor 9*/metabolism, Animals ; Mice ; Male ; Mitochondria/metabolism ; Mice, Inbred C57BL ; Diabetes Mellitus, Experimental/metabolism ; Signal Transduction ; Oxidative Stress ; Proteolysis ; Myocytes, Cardiac/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitin-Protein Ligases/genetics ; Disease Models, Animal ; Apoptosis ; Humans
مستخلص: Introduction: Targeted protein degradation represents a promising therapeutic approach, while diabetic cardiomyopathy (DCM) arises as a consequence of aberrant insulin secretion and impaired glucose and lipid metabolism in the heart..
Objectives: Considering that the Toll-like receptor 9 (TLR9) signaling pathway plays a pivotal role in regulating energy metabolism, safeguarding cardiomyocytes, and influencing glucose uptake, the primary objective of this study was to investigate the impact of TLR9 on diabetic cardiomyopathy (DCM) and elucidate its underlying mechanism.
Methods: Mouse model of DCM was established using intraperitoneal injection of STZ, and mice were transfected with adeno-associated virus serotype 9-TLR9 (AAV9-TLR9) to assess the role of TLR9 in DCM. To explore the mechanism of TLR9 in regulating DCM disease progression, we conducted interactome analysis and employed multiple molecular approaches.
Results: Our study revealed a significant correlation between TLR9 expression and mouse DCM. TLR9 overexpression markedly mitigated cardiac dysfunction, myocardial fibrosis, oxidative stress, and apoptosis in DCM, while inflammation levels remained relatively unaffected. Mechanistically, TLR9 overexpression positively modulated mitochondrial bioenergetics and activated the AMPK-PGC1a signaling pathway. Furthermore, we identified Triad3A as an interacting protein that facilitated TLR9's proteasomal degradation through K48-linked ubiquitination. Inhibiting Triad3A expression improved cardiac function and pathological changes in DCM by enhancing TLR9 activity.
Conclusions: The findings of this study highlight the critical role of TLR9 in maintaining cardiac function and mitigating pathological alterations in diabetic cardiomyopathy. Triad3A-mediated regulation of TLR9 expression and function has significant implications for understanding the pathogenesis of DCM. Targeting TLR9 and its interactions with Triad3A may hold promise for the development of novel therapeutic strategies for diabetic cardiomyopathy. Further research is warranted to fully explore the therapeutic potential of TLR9 modulation in the context of cardiovascular diseases.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Production and hosting by Elsevier B.V.)
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فهرسة مساهمة: Keywords: Diabetic cardiomyopathy; Mitochondrial bioenergetics; Toll-like receptor 9; Triad3A; Ubiquitination
المشرفين على المادة: 0 (Toll-Like Receptor 9)
0 (Tlr9 protein, mouse)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)
تواريخ الأحداث: Date Created: 20230825 Date Completed: 20240624 Latest Revision: 20240721
رمز التحديث: 20240721
مُعرف محوري في PubMed: PMC11258663
DOI: 10.1016/j.jare.2023.08.015
PMID: 37625569
قاعدة البيانات: MEDLINE
الوصف
تدمد:2090-1224
DOI:10.1016/j.jare.2023.08.015