Insulin augments matrix metalloproteinase-9 expression in monocytes.
OBJECTIVE
Insulin resistance and hyperinsulinemia are major causes of cardiovascular morbidity and mortality. Matrix metalloproteinases (MMPs), highly expressed in activated mononuclear cells in vulnerable atherosclerotic lesions, are the main proteolytic enzymes controlling plaque stability. The aim of this study was to investigate the regulation of monocyte MMP-9 by insulin.


RESULTS
Stimulation of MMP-9 expression by insulin was time- and concentration-dependent in human monocytic THP-1 cells. Inhibition of insulin receptor (IR) maturation via inhibition of its activating convertase furin with the pharmacological furin-inhibitor decanoyl-RVKR-chloromethylketone, as well as blocking of IGF-1R function with a IGF-1R blocking antibody, demonstrated that insulin mediates increases in MMP-9 via IR activation. Inhibition of insulin's "metabolic" phosphatidylinositol 3-kinase signaling with wortmannin (50 nmol/L) or LY294002 (2.5 micromol/L) did not prevent insulin-dependent MMP-9 induction. In contrast inhibition of insulin's "mitogenic" Ras-Raf-mitogen-activated protein kinase-kinase pathways with PD98059 (15 micromol/L) or U0126 (2 micromol/L) inhibited insulin-induced MMP-9 gelatinolytic activity in THP-1 cells. Likewise, PD98059 inhibited insulin augmented MMP-9 levels in primary human monocytes, whereas wortmannin had no effect.


CONCLUSIONS
This study demonstrates that insulin can induce MMP-9 via mitogenic signaling pathways in monocytes, whereas phosphatidylinositol 3-kinase-dependent signaling, typically altered in insulin resistance, is not required. Induction of MMP-9 by insulin may potentially contribute to a pro-inflammatory state and the increased cardiovascular morbidity and mortality in type 2 diabetics.
Fischoeder
Arne
A
Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany.
Meyborg
Heike
H
Stibenz
Dietger
D
Fleck
Eckart
E
Graf
Kristof
K
Stawowy
Philipp
P
D000730:Androstadienes / Q000494:pharmacology; D019138:Antibodies, Blocking / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000276:immunology / Q000494:pharmacology*; D007333:Insulin Resistance; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology*; D009570:Nitriles / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D011972:Receptor, Insulin / Q000378:metabolism; D013268:Stimulation, Chemical; D013997:Time Factors; D000077191:Wortmannin
D000730:Androstadienes; D019138:Antibodies, Blocking; D002070:Butadienes; D005419:Flavonoids; D007004:Hypoglycemic Agents; D007328:Insulin; D009570:Nitriles; C113580:U 0126; D011972:Receptor, Insulin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D010741:Phospholipases A; D020780:Matrix Metalloproteinase 9; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin