The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
Notch ligand Delta-like 4 blockade attenuates atherosclerosis and metabolic disorders
Open accessAbstract
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, high-cholesterol 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.
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Cites
Inflammation and metabolic disorders
Hotamisligil, G. S. (2006) · Nature · doi:10.1038/nature05485 · Cited by 9,199
Exploring the full spectrum of macrophage activation
Mosser, D. M., & Edwards, J. P. (2008) · Nature Reviews Immunology · doi:10.1038/nri2448 · Cited by 9,144
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Macrophage-specific PPARγ controls alternative activation and improves insulin resistance
Odegaard, J. I., Ricardo-Gonzalez, R. R., Goforth, M. H., Morel, C. R., Subramanian, V., Mukundan, L., Eagle, A. R., Vats, D., Brombacher, F., Ferrante, A. W., et al. (2007) · Nature · doi:10.1038/nature05894 · Cited by 2,107
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Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis
Ridgway, J., Zhang, G., Wu, Y., Stawicki, S., Liang, W.-C., Chanthery, Y., Kowalski, J., Watts, R. J., Callahan, C., Kasman, I., et al. (2006) · Nature · doi:10.1038/nature05313 · Cited by 986
Angiogenesis modulates adipogenesis and obesity
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“Dll4 blockade disrupts angiogenesis and inhibits cancer growth by induction of hypoxia (10–12), and evidence links angiogenesis with adipose tissue development (65), fat accumulation, and insulin resistance (66).”
BackgroundKang, K., Reilly, S. M., Karabacak, V., Gangl, M. R., Fitzgerald, K., Hatano, B., & Lee, C.-H. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.04.002 · Cited by 699
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Cited by
Inflammation and atherosclerosis: signaling pathways and therapeutic intervention
Kong, P., Cui, Z.-Y., Huang, X.-F., Zhang, D.-D., Guo, R.-J., & Han, M. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00955-7 · Cited by 1,183
Macrophages as a therapeutic target to promote diabetic wound healing
Sharifiaghdam, M., Shaabani, E., Faridi-Majidi, R., De Smedt, S. C., Braeckmans, K., & Fraire, J. C. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.07.016 · Cited by 573
Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity
Bi, P., Shan, T., Liu, W., Yue, F., Yang, X., Liang, X.-R., Wang, J., Li, J., Carlesso, N., Liu, X., et al. (2014) · Nature Medicine · doi:10.1038/nm.3615 · Cited by 267
γ-secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor
Kim, K., Goldberg, I. J., Graham, M. J., Sundaram, M., Bertaggia, E., Lee, S. X., Qiang, L., Haeusler, R. A., Metzger, D., Chambon, P., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.02.010 · Cited by 26
Metadata
- Authors
- Fukuda, D., Aikawa, E., Swirski, F. K., Novobrantseva, T. I., Kotelianski, V., Gorgun, C. Z., Chudnovskiy, A., Yamazaki, H., Croce, K., Weissleder, R., Aster, J. C., Hotamisligil, G. S., Yagita, H., & Aikawa, M.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2012-06-13
- Volume
- 109
- Issue
- 27
- Pages
- E1868-77
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2142653769
- Cited by
- 167
- References
- 13
- FWCI
- 4.56
- Type
- journal article
- Language
- en
- Open access
- green
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- Fukuda, D., Aikawa, E., Swirski, F. K., Novobrantseva, T. I., Kotelianski, V., Gorgun, C. Z., Chudnovskiy, A., Yamazaki, H., Croce, K., Weissleder, R., Aster, J. C., Hotamisligil, G. S., Yagita, H., & Aikawa, M. (2012). Notch ligand Delta-like 4 blockade attenuates atherosclerosis and metabolic disorders. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1116889109
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