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Published on: April 3, 2017
Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis
Niranjana Natarajan1, Jonathan Florentin1, Ebin Johny1
1Pittsburgh 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.
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.
Insights
Vascular cell adhesion molecule 1 (VCAM-1) drives mitochondrial DNA synthesis in macrophages, worsening atherosclerosis. Inhibiting VCAM-1 in macrophages reduces inflammation and disease severity, revealing a key pathway in cardiovascular disease progression.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cellular Metabolism
Background:
- Cellular metabolism significantly influences inflammation and atherosclerosis progression.
- The specific role of mitochondrial DNA (mtDNA) synthesis in macrophage function and atherosclerosis remains unclear.
Purpose of the Study:
- To investigate the link between mitochondrial DNA synthesis, macrophage function, and atherosclerosis pathology.
- To elucidate the molecular mechanisms by which mitochondrial DNA synthesis is regulated in atherosclerotic macrophages.
Main Methods:
- Transcriptomic analysis of plaque macrophages and spatial single-cell transcriptomics of atherosclerotic plaques.
- Functional experiments in human and mouse models, including Apoe-/- mice lacking Vcam1 in macrophages.
- Assessment of VCAM-1 expression correlation with plaque characteristics and oxidative damage in human carotid plaques.
Main Results:
- Vascular cell adhesion molecule 1 (VCAM-1) triggers mitochondrial DNA (mtDNA) synthesis in atherosclerotic plaque macrophages under inflammatory conditions.
- VCAM-1 activates C/EBPα, leading to increased expression of Cmpk2 and Pgc1a, promoting mtDNA synthesis and STING-mediated inflammation.
- Mice lacking VCAM-1 in macrophages exhibit reduced atherosclerosis and inflammation; VCAM-1 expression correlates with plaque severity and DNA damage in humans.
Conclusions:
- Macrophage VCAM-1 plays a critical role in promoting inflammation and atherogenesis through a VCAM-1-C/EBPα-mtDNA synthesis-STING pathway.
- This pathway represents a self-acerbating mechanism contributing to cardiovascular disease.
- Targeting macrophage VCAM-1 may offer a therapeutic strategy for atherosclerosis.
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