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Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis.
Natarajan, Niranjana; Florentin, Jonathan; Johny, Ebin; Xiao, Hanxi; O'Neil, Scott Patrick; Lei, Liqun; Shen, Jixing; Ohayon, Lee; Johnson, Aaron R; Rao, Krithika; Li, Xiaoyun; Zhao, Yanwu; Zhang, Yingze; Tavakoli, Sina; Shiva, Sruti; Das, Jishnu; Dutta, Partha.
Afiliación
  • Natarajan N; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
  • Florentin J; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
  • Johny E; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
  • Xiao H; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
  • O'Neil SP; Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
  • Lei L; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • Shen J; Joint CMU-Pitt PhD program in Computational Biology, Pittsburgh, PA, USA.
  • Ohayon L; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
  • Johnson AR; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
  • Rao K; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
  • Li X; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
  • Zhao Y; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
  • Zhang Y; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
  • Tavakoli S; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
  • Shiva S; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
  • Das J; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
  • Dutta P; Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
Nat Commun ; 15(1): 7337, 2024 Aug 26.
Article en En | MEDLINE | ID: mdl-39187565
ABSTRACT
There is a large body of evidence that cellular metabolism governs inflammation, and that inflammation contributes to the progression of atherosclerosis. However, whether mitochondrial DNA synthesis affects macrophage function and atherosclerosis pathology is not fully understood. Here we show, by transcriptomic analyzes of plaque macrophages, spatial single cell transcriptomics of atherosclerotic plaques, and functional experiments, that mitochondrial DNA (mtDNA) synthesis in atherosclerotic plaque macrophages are triggered by vascular cell adhesion molecule 1 (VCAM-1) under inflammatory conditions in both humans and mice. Mechanistically, VCAM-1 activates C/EBPα, which binds to the promoters of key mitochondrial biogenesis genes - Cmpk2 and Pgc1a. Increased CMPK2 and PGC-1α expression triggers mtDNA synthesis, which activates STING-mediated inflammation. Consistently, atherosclerosis and inflammation are less severe in Apoe-/- mice lacking Vcam1 in macrophages. Downregulation of macrophage-specific VCAM-1 in vivo leads to decreased expression of LYZ1 and FCOR, involved in STING signalling. Finally, VCAM-1 expression in human carotid plaque macrophages correlates with necrotic core area, mitochondrial volume, and oxidative damage to DNA. Collectively, our study highlights the importance of macrophage VCAM-1 in inflammation and atherogenesis pathology and proposes a self-acerbating pathway involving increased mtDNA synthesis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN Mitocondrial / Molécula 1 de Adhesión Celular Vascular / Aterosclerosis / Placa Aterosclerótica / Inflamación / Macrófagos / Proteínas de la Membrana Límite: Animals / Female / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN Mitocondrial / Molécula 1 de Adhesión Celular Vascular / Aterosclerosis / Placa Aterosclerótica / Inflamación / Macrófagos / Proteínas de la Membrana Límite: Animals / Female / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido