title: Interleukin 6 destabilizes atherosclerotic plaques by downregulating prolyl-4-hydroxylase α1 via a mitogen-activated protein kinase and c-Jun pathway.
abstract: Interleukin 6 (IL-6) is a pivotal cytokine that regulates extracellular matrix metabolism by ameliorating the modification of collagen content, important in fibrous caps of atherosclerotic plaque. Prolyl-4-hydroxylase α1 (P4Hα1) is a key intracellular enzyme required for synthesis of collagen in animals. We investigated the relationship of IL-6 and P4Hα1 in atherosclerosis-prone mice and human aortic smooth muscle cells (HASMCs). Apolipoprotein E (ApoE)-/- mice were fed a high-fat diet and a perivascular constrictive silica collar was placed on the right common carotid artery to induce atherosclerotic lesions, then mice were divided into two groups for transfection with empty lentivirus or IL-6 lentivirus. HASMCs were transfected with small interfering RNA or treated with recombinant human IL-6. IL-6 significantly downregulated collagen, P4Hα1 and smooth muscle cell contents in atherosclerotic mouse arteries. Macrophage and lipid contents in the atherosclerotic area were significantly increased with IL-6 treatment. IL-6 significantly downregulated P4Hα1 expression in HASMCs through an RAF-MEK1/2-ERK1/2 mitogen-activated protein kinase (MAPK) pathway, and c-Jun was involved in the process. Our findings highlight IL-6 destabilize atherosclerotic plaques in mice by downregulating P4Hα1 via an RAF-MEK1/2-ERK1/2 MAPK and c-Jun pathway.
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Shandong University Qilu Hospital, Jinan, Shandong 250012, PR China.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: Xiao-zhen
authors.initials: XZ
authors.lastname: Huang
authors.forename: Xiao-nan
authors.initials: XN
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Feng
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Xiao-jun
authors.initials: XJ
authors.lastname: Cai
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Xiao-ling
authors.initials: XL
authors.lastname: Liu
authors.forename: Ming-xiang
authors.initials: MX
authors.lastname: Zhang
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xing-li
authors.initials: XL
authors.lastname: Wang
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001483:Base Sequence; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection
chemical_list: D001057:Apolipoproteins E; C508600:IL6 protein, human; D015850:Interleukin-6; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C510863:P4HA1 protein, human; D011393:Procollagen-Proline Dioxygenase; D048031:JNK Mitogen-Activated Protein Kinases