INHIBITING DCLK1 IN MACROPHAGES MIGHT BE A CURE FOR ATHEROSCLEROSIS

Atherosclerosis is a chronic cardiovascular disease that has become common, especially among the older population. Even though it can be prevented with a good diet, people of generally good health above the age of 50 have a 50% chance of developing atherosclerosis. 

Atherosclerosis is believed to be caused due to the inflammation of endothelial cells of the artery and then the accumulation of Low Density Lipoproteins (LDLs) in the damaged area which in turn deploys macrophages. The macrophages digest the cholesterol molecules, and as a result their configuration changes and leads to the formation of a plaque. The plaque eventually breaks out and blocks the artery thereby also blocking blood flow hence leading to death of the tissue that receives blood from that artery. Blocked blood flow can lead to heart attacks, strokes, critical limb ischemia, and the list adds on. Currently, there is no known cure for atherosclerosis but it can be slowed down by statin drugs and dietary changes. However, identifying the mechanism of the inflammatory responses and their regulatory factors can provide targets to treat atherosclerosis. 

Researchers at the Wenzhou Medical University (WMU), suspected the role of DCLK1(Doublecortin like Kinase 1)  in atherosclerosis. The suspicion was mainly due to previous research papers published on its role in neurogenesis and carcinogenesis. This suspicion led the researchers to evaluate the role of DCLK1 in atherosclerosis. 

DCLK1 is a microtubule-associated serine/threonine kinase found in the nervous system, nonproliferating cells of the gastrointestinal tract, and pancreatic stem cells. It was first recognized in the nervous system for its management of microtubule polymerization and neuronal migration. Several studies also show that DCLK1 might have significant roles in tumorigenesis i.e. it promotes cancer by creating an inflammatory tumor microenvironment, which inspired the researchers of WMU to evaluate its role in the inflammation of endothelial cells of the artery. In spite of the developments made in the research, the exact pathway of how DCLK1 regulates inflammation remains ambiguous. 

After a series of experimental data, the researchers of WMU provide core takeaways for further research and development regarding DCLK1. Their studies show that DCLK1 is upregulated in the macrophages of atherosclerotic lesions of HFD (high-fat diet) fed ApoE−/− mice than in normal mice. Further, macrophage-specific DCLK1 knockout reduced plaques in HFD-fed ApoE−/− mice, suppressed inflammatory cell infiltration, and alleviated inflammatory response in the aorta. ApoE is a gene that encodes for apolipoprotein E which combines with fats to form lipoproteins and transports cholesterol through blood vessels. ApoE−/− mice are mice developed by homologous recombination to be specifically used as an atherosclerosis model.

 The regulation of macrophage-specific DCLK1 was then investigated by inducing oxidized LDL to isolations of mouse peritoneal macrophages whose DCLK1 was deleted, the results showed a reduction of inflammatory response by inhibiting NF-κB (nuclear factor kappa B, transcription factor that regulates expression of inflammatory genes) activation. Mass spectrometry data demonstrated that DCLK1 directly interferes with IKKβ, a known inhibitor of NF-κB to promote NF-κB activation.

In addition to the above findings, the researchers deployed a known small molecule inhibitor of DCLK1 which weakens NF-κB activation and reduces inflammation in oxidized LDL challenged macrophages, thereby preventing atherosclerotic progression in mice. Although the researchers state limitations to the study, the specific domains through which DCLK1 and IKKβ interact and the mechanism behind the upregulation of DCLK1 in macrophages induced with oxidized LDL have not been identified.  

The findings expand the knowledge of the role of DCLK1 in inflammatory responses in atherosclerosis as an activator of IKKβ/NF-κB and unveil a potential therapeutic target for inflammatory atherosclerosis.

REFERENCE: 

Huang, Z., Shen, S., Han, X., Li, W., Luo, W., Lin, L., ... & Liang, G. (2023). Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses. EMBO Molecular Medicine, e17198.

 IMAGE CREDITS

Cover image: https://med.stanford.edu/news/all-news/2020/06/unregulated-artery-cell-growth-may-drive-atherosclerosis.html