Kappert Kai, Meyborg Heike, Clemenz Markus, Graf Kristof, Fleck Eckart, Kintscher Ulrich, Stawowy Philipp
Center for Cardiovascular Research, Institute of Pharmacology, Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Hessische Str. 3-4, D-10115 Berlin, Germany.
Biochem Biophys Res Commun. 2008 Jan 18;365(3):503-8. doi: 10.1016/j.bbrc.2007.11.006. Epub 2007 Nov 20.
Mononuclear cells (MNCs) are the primary cell type involved in the pro-inflammatory state of obesity-linked insulin-resistance, and atherosclerosis. Increased serum levels of MMP-9 are reported in insulin-resistant type 2 diabetic patients. Here we demonstrate insulin facilitating human monocytic THP-1 cell chemotaxis via prolonged Erk1/2-dependent induction of MMP-9. In vivo, significantly increased serum levels of MMP-9 were found in obesity-induced hyperinsulinemic C57BL/J6 mice, which were diminished by treatment with the anti-diabetic PPARgamma-ligand pioglitazone. In line with this, pioglitazone inhibited Erk1/2-phosphorylation and subsequent insulin-dependent MMP-9 synthesis in THP-1 cells. Thus, insulin increases MMP-9 gelatinolytic activity in monocytic cells, which results in accelerated chemotaxis. Hyperinsulinemia is associated with enhanced MMP-9 serum levels, potentially facilitating monocyte migration to and infiltration of adipose tissue and the arterial wall, thereby contributing to the increased cardiovascular risk in obese, hyperinsulinemic patients.
单核细胞（MNCs）是参与肥胖相关胰岛素抵抗和动脉粥样硬化促炎状态的主要细胞类型。据报道，胰岛素抵抗的2型糖尿病患者血清MMP-9水平升高。在此，我们证明胰岛素通过延长Erk1/2依赖性诱导MMP-9促进人单核细胞THP-1细胞趋化。在体内，肥胖诱导的高胰岛素血症C57BL/J6小鼠血清MMP-9水平显著升高，而抗糖尿病PPARγ配体吡格列酮治疗可降低该水平。与此一致，吡格列酮抑制THP-1细胞中Erk1/2磷酸化及随后的胰岛素依赖性MMP-9合成。因此，胰岛素增加单核细胞中MMP-9的明胶酶活性，导致趋化加速。高胰岛素血症与血清MMP-9水平升高相关，可能促进单核细胞向脂肪组织和动脉壁的迁移和浸润，从而增加肥胖、高胰岛素血症患者的心血管风险。
