The subendothelial extracellular matrix modulates JNK activation by flow.

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Cellular Biology

Background:

• Atherosclerosis involves artery wall inflammation, particularly at sites with disturbed blood flow.
• c-Jun NH(2)-terminal kinase (JNK) is a key regulator of inflammatory gene expression in endothelial cells influenced by flow.

Purpose of the Study:

• To investigate the matrix specificity of JNK activation in response to fluid shear stress.
• To identify the molecular mechanisms underlying flow-induced JNK activation in endothelial cells.
• To correlate in vitro findings with in vivo observations in early atherosclerosis.

Main Methods:

• Assessing JNK activation on different extracellular matrix proteins (fibronectin, basement membrane, collagen) under laminar and oscillatory flow conditions.
• Investigating the roles of integrin ligation, MKK4, and p21-activated kinase in flow-induced JNK activation.
• Examining JNK activation and fibronectin deposition in vivo at sites of early atherogenesis.

Main Results:

• JNK activation is matrix-specific, showing enhanced responses on fibronectin compared to other matrices.
• Flow-induced JNK activation on fibronectin requires integrin ligation, MKK4, and p21-activated kinase.
• In vivo, JNK activation in early atherosclerosis correlates with fibronectin deposition, and inhibiting p21-activated kinase reduces this activation.

Conclusions:

• JNK activation in response to fluid shear stress is a matrix-specific inflammatory event.
• Fibronectin plays a critical role in mediating flow-induced JNK activation in endothelial cells.
• These findings elucidate matrix-specific pathways involved in regulating inflammatory responses to shear stress in atherosclerosis.