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.