Notch ligand Delta-like 4 blockade attenuates atherosclerosis and metabolic disorders

Daiju Fukuda, Elena Aikawa, Filip K. Swirski, Tatiana I. Novobrantseva, Victor Kotelianski, Cem Z. Gorgun, Aleksey Chudnovskiy, Hiroyuki Yamazaki, Kevin Croce, Ralph Weissleder, Jon C. Aster, Gökhan S. Hotamisligil, Hideo Yagita, Masanori Aikawa

Research output: Contribution to journalArticlepeer-review

134 Scopus citations


Atherosclerosis and insulin resistance are major components of the cardiometabolic syndrome, a global health threat associated with a systemic inflammatory state. Notch signaling regulates tissue development and participates in innate and adaptive immunity in adults. The role of Notch signaling in cardiometabolic inflammation, however, remains obscure. We noted that a high-fat, highcholesterol diet increased expression of the Notch ligand Delta-like 4 (Dll4) in atheromata and fat tissue in LDL-receptor-deficient mice. Blockade of Dll4-Notch signaling using neutralizing anti-Dll4 antibody attenuated the development of atherosclerosis, diminished plaque calcification, improved insulin resistance, and decreased fat accumulation. These changes were accompanied by decreased macrophage accumulation, diminished expression of monocyte chemoattractant protein-1 (MCP-1), and lower levels of nuclear factor- κB (NF-κB) activation. In vitro cell culture experiments revealed that Dll4-mediated Notch signaling increases MCP-1 expression via NF-κB, providing a possible mechanism for in vivo effects. Furthermore, Dll4 skewed macrophages toward a proinflammatory phenotype ("M1"). These results suggest that Dll4-Notch signaling plays a central role in the shared mechanism for the pathogenesis of cardiometabolic disorders.

Original languageEnglish
Pages (from-to)E1868-E1877
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number27
StatePublished - 3 Jul 2012
Externally publishedYes


  • Biotherapy
  • Cardiovascular diseases
  • Collagen
  • Diabetes mellitus
  • Obesity


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