Journal Article

Cardiotrophin-1 Induces Matrix Metalloproteinase-1 in Human Aortic Endothelial Cells

Ichiki, Tomoko, Hamasaki, Shuichi, Tokito, Akinori, Jougasaki, Michihisa

2013

Overview

Rupture of an atherosclerotic plaque is a key event in the development of cardiovascular disorders, in which matrix metalloproteinase-1 (MMP-1) plays a crucial role by degradation of extracellular matrix resulting in plaque instability. Cardiotrophin-1 (CT-1), a member of interleukin-6-type proinflammatory cytokines, has potent cardiovascular actions and is highly expressed in vascular endothelium, however its role in atherosclerosis has not been fully elucidated to date. The present study was designed to investigate whether CT-1 induces MMP-1 in human aortic endothelial cells (HAECs). Ribonuclease protection assay demonstrated that MMP-1 gene level in HAECs was enhanced by the treatment of CT-1 in a dose- and time-dependent manner. Immunocytochemical staining, Western immunoblot analysis and enzyme-linked immunosorbent assay revealed that CT-1 augmented MMP-1 protein synthesis and secretion. MMP-1 activity assay revealed that MMP-1 present in the supernatant of HAECs was exclusively precursor form. Casein zymography disclosed proteolytic activity in the supernatant of HAECs, which was enhanced by CT-1 treatment. Furthermore, pharmacological inhibitor study indicated the important roles of extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen-activated protein (MAP) kinase, c-Jun N-terminal kinase (JNK) and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways in mediating CT-1-induced MMP-1 gene and protein expression. These data reveal for the first time that CT-1 induces the proteolytic potential in HAECs by upregulating MMP-1 expression through ERK1/2, p38 MAP kinase, JNK and JAK/STAT pathways, and suggest that CT-1 may play an important role in the pathophysiology of atherosclerosis and plaque instability.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Angina pectoris / Aorta / Aorta - cytology / Arteriosclerosis / Assaying / Atherosclerosis / Biology / c-Jun protein / Casein / Chemokine CCL2 - metabolism / Cytochemistry / Cytokines / Cytokines - pharmacology / Disease / Endothelial cells / Endothelial Cells - drug effects / Endothelial Cells - enzymology / Endothelium / Enzyme Induction - drug effects / Enzyme-linked immunosorbent assay / Extracellular matrix / Extracellular signal-regulated kinase / Fibroblasts / Gene expression / Growth factors / Hospitals / Humans / Inflammation / Interleukin 6 / Interleukin-6 - metabolism / Interleukins / Interstitial collagenase / Janus kinase / Janus Kinases - metabolism / JNK Mitogen-Activated Protein Kinases - metabolism / JNK protein / Kinases / Leukemia / Ligands / MAP kinase / MAP Kinase Signaling System - drug effects / Matrix metalloproteinase / Matrix Metalloproteinase 1 - biosynthesis / Matrix Metalloproteinase 1 - genetics / Matrix Metalloproteinase 1 - metabolism / Medicine / Metalloproteinase / Mitogens / Models, Biological / Pharmacology / Polyclonal antibodies / Protein biosynthesis / Protein synthesis / Proteins / Proteolysis / Proteolysis - drug effects / R&D / Research & development / Ribonuclease / RNA, Messenger - genetics / RNA, Messenger - metabolism / Rodents / Signal transduction / Signaling / Smooth muscle / Stability / STAT Transcription Factors - metabolism / Subcellular Fractions - drug effects / Subcellular Fractions - metabolism / Transcription factors / Transducers