Background
-Although the role of thrombin in atherothrombosis is well studied, its role in the pathogenesis of diet-induced atherosclerosis is not known.
Methods
-Using a mouse model of diet-induced atherosclerosis and molecular biological approaches, here we have explored the role of thrombin and its G protein-coupled receptor (GPCR) signaling in diet-induced atherosclerosis.
Results
-In exploring the role of GPCR signaling in atherogenesis, we found that thrombin triggers foam cell formation via inducing CD36 expression and these events require Par1-mediated Gα12-Pyk2-Gab1-PKCθ-dependent ATF2 activation. Genetic deletion of PKCθ in ApoE-/- mice reduced western diet (WD)-induced plaque formation. Furthermore, thrombin induced Pyk2, Gab1, PKCθ and ATF2 phosphorylation, CD36 expression and foam cell formation in peritoneal macrophages of ApoE-/- mice. On the other hand, thrombin only stimulated Pyk2 and Gab1 but not ATF2 phosphorylation or its target gene CD36 expression in the peritoneal macrophages of ApoE-/-:PKCθ-/- mice and it had no effect on foam cell formation. In addition, the aortic root cross sections of WD-fed ApoE-/- mice showed increased Pyk2, Gab1, PKCθ and ATF2 phosphorylation and CD36 expression as compared to ApoE-/-:PKCθ-/- mice. Furthermore, while the monocytes from peripheral blood and aorta of WD-fed ApoE-/- mice were found to contain more of Ly6Chi cells than Ly6Clo cells, the monocytes from WD-fed ApoE-/-:PKCθ-/- mice were found to contain more of Ly6Clo cells than Ly6Chi cells. Interestingly, the Ly6Chi cells showed higher CD36 expression with enhanced capacity to form foam cells as compared to Ly6Clo cells.
Conclusions
-The above findings reveal for the first time that thrombin-mediated Par1-Gα12 signaling via targeting Pyk2-Gab1-PKCθ-ATF2-dependent CD36 expression might be playing a crucial role in diet-induced atherogenesis.
Pharmacology, Toxicology and Pharmaceutical Science
2
6%
Nursing and Health Professions
1
3%
Agricultural and Biological Sciences
1
3%
Other
2
6%
Unknown
15
43%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 8. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 15 December 2018.
All research outputs
#5,642,077
of 29,591,028 outputs
Outputs from Circulation
#11,497
of 25,890 outputs
Outputs of similar age
#85,627
of 347,280 outputs
Outputs of similar age from Circulation
#120
of 178 outputs
Altmetric has tracked 29,591,028 research outputs across all sources so far. Compared to these this one has done well and is in the 80th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 25,890 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 31.8. This one has gotten more attention than average, scoring higher than 55% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 347,280 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 75% of its contemporaries.
We're also able to compare this research output to 178 others from the same source and published within six weeks on either side of this one. This one is in the 32nd percentile – i.e., 32% of its contemporaries scored the same or lower than it.
