LCK inhibitor attenuates atherosclerosis in ApoE-/- mice via regulating T cell differentiation and reverse cholesterol transport.

Abstract

Lots of studies demonstrated that CD4+ T cells regulate the development of atherosclerosis (AS). Previously, we reported that LCK, a key molecule in activation of T cell receptor (TCR) signalling and T cells, adversely affects reverse cholesterol transport (RCT), which ameliorates AS in vitro. To investigate the effect of LCK on AS in vivo, we injected the LCK inhibitor, PP2, into ApoE-/- mice fed a chow diet or a high-fat diet (HFD). Although, AS plaques were not affected by PP2 in chow diet-fed mice, PP2 significantly reduced the lesion percentage and necrotic core areas in HFD-fed mice. We further analysed the plaque contents and found that the accumulation of lipids and macrophages were decreased, while the contents of collagen and smooth muscle cells were increased by the LCK inhibitor. Thus, inhibiting LCK enhanced the plaque stability. We also found the LCK inhibitor improved cholesterol efflux capacity of HDL and up-regulated RCT regulatory proteins in the spleen. Moreover, inhibiting LCK regulated differentiation of T cells by increasing regulatory T (Treg) cells and decreasing the number of T helper 1 (Th1) cells in the aorta, thymus and spleen. Consistent with these results, infiltration of CD4+ T cells in plaques, secretion of pro-atherosclerotic cytokines, INF-γ and TNF-α synthesized mostly by Th1 cells, and the activation of PI3K/AKT/mTOR signalling were inhibited by the LCK inhibitor. Moreover, the effect of LCK inhibitor on the ratio of Th1 to Treg cells were compromised by activation of mTOR. Together, these data indicate that inhibiting LCK in TCR signalling attenuated the development of AS and promoted plaque stability. Improving RCT by upregulating RCT regulatory proteins and decreasing the Th1/Treg ratio by inhibiting PI3K/AKT/mTOR signalling may contribute to the anti-atherosclerotic effects of LCK inhibition.

• Authors: Jichen Liu, Zhongzhou Guo, Yanan Zhang, Tongwei Wu, Yusheng Ma, Wenyan Lai, Zhigang Guo
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 139 Pg. 87-97 (02 2020) ISSN: 1095-8584 [Electronic] England
• PMID: 31972265 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Apolipoproteins E
• Lipids
• Protein Kinase Inhibitors
• Cholesterol
• Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Animals
• Apolipoproteins E (deficiency)
• Atherosclerosis (blood, metabolism, pathology)
• Biological Transport (drug effects)
• Cell Differentiation (drug effects)
• Cholesterol (metabolism)
• Diet, High-Fat
• Lipids (blood)
• Lymphocyte Specific Protein Tyrosine Kinase p56(lck) (antagonists & inhibitors, metabolism)
• Male
• Mice
• Models, Biological
• Necrosis
• Phosphatidylinositol 3-Kinases (metabolism)
• Plaque, Atherosclerotic (blood, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• RAW 264.7 Cells
• Signal Transduction (drug effects)
• T-Lymphocytes (cytology, drug effects, metabolism)
• TOR Serine-Threonine Kinases (metabolism)
• Up-Regulation (drug effects)