Research Paper Volume 13, Issue 18 pp 22412—22431
Pim-2 kinase inhibits inflammation by suppressing the mTORC1 pathway in atherosclerosis
- 1 The Department of Cardiovascular Medicine, The Affiliated Dongguan Hospital of Southern Medical University, Dongguan, Guangdong, China
- 2 The Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- 3 The Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- 4 The College of Pharmacy, Nanchang University, Nanchang, Jiangxi, China
Received: July 1, 2021 Accepted: September 7, 2021 Published: September 21, 2021https://doi.org/10.18632/aging.203547
How to Cite
Copyright: © 2021 Liao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Background: Inflammatory immunity theory has raised considerable concern in the pathogenesis of atherosclerosis. Proviral integration site of murine 2 (Pim-2) kinases functions in apoptosis pathways and the anti-inflammatory response. Here, we investigated whether Pim-2 kinase inhibits atherosclerotic inflammation by suppressing the mTORC1 pathway.
Methods: An atherosclerosis animal model was established by feeding ApoE -/- mice a high-fat diet. THP-1-derived macrophages were subjected to ox-LDL (50 μg/ml, 24h) conditions in vitro to mimic the in vivo conditions.
Result: The protein expression of Pim-2 was upregulated in ox-LDL-treated THP-1-derived macrophages and an atherosclerotic mouse model. Additionally, ox-LDL upregulated the protein expression of p-mTOR, p-S6K1 and p-4EBP1, intracellular lipid droplets, free cholesterol and cholesterylester and the mRNA expression of inflammatory cytokines, including IL-6, MCP-1, TLR-4 and TNF-α, in THP-1-derived macrophages. Functionally, overexpressed Pim-2 (Pim-2 OE) attenuated atherosclerotic inflammation associated with the mTORC1 signaling pathway in vitro and in vivo, whereas knocked down Pim-2 (Pim-2 KD) markedly promoted atherosclerotic inflammation associated with upregulation of the mTORC1 signaling pathway. The plaque areas and lesions in the whole aorta and aortic root sections were alleviated in ApoE -/- mice with Pim-2 OE, but aggravated by Pim-2 KD. Additionally, an mTOR agonist (MHY1485) counteracted the anti-inflammatory effect of Pim-2 in ox-LDL-treated THP-1-derived macrophages after Pim-2 OE, whereas rapamycin rescued atherosclerotic inflammation in ox-LDL-treated THP-1-derived macrophages after Pim-2 KD. Furthermore, si-mTOR and si-Raptor alleviated the atherosclerotic proinflammatory effect in ox-LDL-treated THP-1-derived macrophages in a the background of Pim-2 KD.
Conclusions:These results indicated that Pim-2 kinase inhibits atherosclerotic inflammation by suppressing the mTORC1 pathway.