title: Insulin inhibits inflammation and promotes atherosclerotic plaque stability via PI3K-Akt pathway activation.
abstract: Toll-like receptor (TLR) 4 induced inflammation was reported to play an important role in atherosclerotic plaque stability. Recent studies indicated that insulin could inhibit inflammation by activating phosphatidylinositol 3-kinase-Akt-dependent (PI3K-Akt) signaling pathway. In the current study, we hypothesized that insulin would inhibit TLR4 induced inflammation via promoting PI3K-Akt activation, thus enhancing the stabilization of atherosclerotic plaques. In order to mimic the process of plaque formation, monocyte-macrophage lineage RAW264.7 were cultured and induced to form foam cells by oxidized LDL (ox-LDL). Oil red O staining results showed that insulin significantly restrained ox-LDL-induced foam cell formation. Analysis of inflammatory reaction during foam cell formation indicated that insulin significantly down-regulated the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6 levels, inhibited TLR4, myeloid differentiation primary response gene (MyD) 88 and nuclear factor (NF)-κB. Further mechanism analysis showed that pretreating with the PI3K blocker, wortmannin dramatically dampened the insulin-induced up-regulation of pAkt expression. Additionally, blockade of PI3K-Akt signaling also dampened the immunosuppression effect brought by insulin. Following the construction of a rodent atherosclerosis model, pretreatment of insulin resulted in an evident decrease in lipid deposition of the blood vessel wall, serum levels of TNF-α and IL-6, and numbers of infiltrated macrophages and foam cells. Taken together, these results suggested that insulin might inhibit inflammation and promote atherosclerotic plaque stability via the PI3K-Akt pathway by targeting TLR4-MyD88-NF-κB signaling. Our findings may provide a potential target for the prevention of cardiovascular disease.
authors.affiliation: Department of Cardiovasology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Cardiovasology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Cardiovasology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: profleeyan@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiovasology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Cardiovasology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Lv
authors.affiliation: Department of Physiology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Cardiovasology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Ma
authors.affiliation: Department of Cardiovasology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Le
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Cardiovasology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Congye
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Cardiovasology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Rongqing
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Cardiovasology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Haichang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cardiovasology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Tao
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D018836:Inflammation Mediators; D007328:Insulin; D008077:Lipoproteins, LDL; D051197:Toll-Like Receptor 4; C099252:oxidized low density lipoprotein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Inflammation; Insulin; PI3K-Akt; Plaque stability; TLR4