Insulin augments matrix metalloproteinase-9 expression in monocytes

Area of Science:

• Cardiovascular Biology
• Endocrinology
• Molecular Cell Biology

Background:

• Insulin resistance and hyperinsulinemia contribute to cardiovascular disease.
• Matrix metalloproteinases (MMPs), particularly MMP-9, are key in atherosclerotic plaque instability.
• Mononuclear cells in atherosclerotic lesions express high levels of MMPs.

Purpose of the Study:

• To investigate how insulin regulates monocyte matrix metalloproteinase-9 (MMP-9) expression.
• To elucidate the specific signaling pathways involved in insulin-induced MMP-9 regulation.

Main Methods:

• Used human monocytic THP-1 cells and primary human monocytes.
• Investigated insulin's effect on MMP-9 expression in a time- and concentration-dependent manner.
• Utilized inhibitors for insulin receptor (IR) maturation, IGF-1R, phosphatidylinositol 3-kinase (PI3K), and Ras-Raf-mitogen-activated protein kinase (MAPK) pathways.

Main Results:

• Insulin dose-dependently increased MMP-9 expression and activity in THP-1 cells.
• Insulin-induced MMP-9 upregulation was mediated via insulin receptor (IR) activation.
• Inhibition of PI3K signaling did not affect insulin-induced MMP-9, while inhibition of Ras-Raf-MAPK pathways blocked it.
• Similar effects were observed in primary human monocytes.

Conclusions:

• Insulin induces MMP-9 in monocytes primarily through mitogenic signaling pathways (Ras-Raf-MAPK).
• Phosphatidylinositol 3-kinase (PI3K) signaling, often altered in insulin resistance, is not required for this induction.
• Insulin-mediated MMP-9 induction may contribute to the pro-inflammatory state and heightened cardiovascular risk in type 2 diabetes.