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Mitochondrial Fission Mediates Endothelial Inflammation

Year: 2020
Type: article
Abstract: Endothelial inflammation and mitochondrial dysfunction have been implicated in cardiovascular diseases, yet, a unifying mechanism tying them together remains limited. Mitochondrial dysfunction is frequently associated with mitochondrial fission/fragmentation mediated by the GTPase Drp1 (dynamin-related protein 1). Nuclear factor (NF)-κB, a master regulator of inflammation, is implicated in endothelial dysfunction and resultant complications. Here, we explore a causal relationship between mitochondrial fission and NF-κB activation in endothelial inflammatory responses. In cultured endothelial cells, TNF-α (tumor necrosis factor-α) or lipopolysaccharide induces mitochondrial fragmentation. Inhibition of Drp1 activity or expression suppresses mitochondrial fission, NF-κB activation, vascular cell adhesion molecule-1 induction, and leukocyte adhesion induced by these proinflammatory factors. Moreover, attenuations of inflammatory leukocyte adhesion were observed in Drp1 heterodeficient mice as well as endothelial Drp1 silenced mice. Intriguingly, inhibition of the canonical NF-κB signaling suppresses endothelial mitochondrial fission. Mechanistically, NF-κB p65/RelA seems to mediate inflammatory mitochondrial fission in endothelial cells. In addition, the classical anti-inflammatory drug, salicylate, seems to maintain mitochondrial fission/fusion balance against TNF-α via inhibition of NF-κB. In conclusion, our results suggest a previously unknown mechanism whereby the canonical NF-κB cascade and a mitochondrial fission pathway interdependently regulate endothelial inflammation.
Source: Hypertension
DOI: 10.1161/hypertensionaha.120.14686
Authors: Steven J. Forrester, Kyle J. Preston, Hannah A. Cooper, Michael J. Boyer, Kathleen M. Escoto, Anthony J. Poltronetti, Katherine J. Elliott, Ryohei Kuroda, Masashi Miyao, Hiromi Sesaki, Tomoko Akiyama, Yayoi Kimura, Victor Rizzo, Rosario Scalia, Satoru Eguchi
Institutions: Temple University, Kyoto University, Johns Hopkins University, Johns Hopkins Medicine, Advanced Medical Research Center, Yokohama City University, Yokohama City University
Language: English
Open Access status: green
Awards: Mechanism of Hypertensive Vascular Remodeling and End-Organ Damage, Mitochondrial fission mediates hypertensive vascular remodeling, Mechanistic Insight into the Novel Role of Exosomes in Vascular Physiology and Pathology, Mitochondrial Quality Control by Drp1, Inflammatory Responses of The Visceral Adipose Tissue Microcirculation, An integrative multi-omic analysis for biomarker discovery in glioblastoma, Regulation of Mitochondrial Division by Phosphatidic Acid, EGF-ADAM17 axis in the pathophysiology of intracranial aneurysm, Vascular signal as a therapeutic target for abdominal aortic aneurysm, The Role of Endothelial Dysfunction and Vascular Inflammation in Hypertensive Vascular Remodeling
OpenAlex ID: W3022863823
FWCI: 4.705
Cites: 52
Cited by: 100
Related to: 10