Neuraminidase inhibition improves endothelial function in diabetic mice

Area of Science:

• Biochemistry
• Cardiovascular Biology
• Endocrinology

Background:

• Plasma neuraminidase activity is elevated in type 2 diabetes (T2D).
• Neuraminidases cleave sialic acids from endothelial glycocalyx structures.
• Elevated neuraminidase may contribute to endothelial dysfunction in T2D.

Purpose of the Study:

• To investigate the role of circulating neuraminidase in endothelial dysfunction in T2D.
• To assess the potential of neuraminidase inhibition as a therapeutic strategy for T2D-associated endothelial dysfunction.

Main Methods:

• Measured plasma neuraminidase activity, nitrite concentrations, and flow-mediated dilation (FMD) in T2D subjects and controls.
• Exposed mouse arteries and cultured endothelial cells to neuraminidase.
• Administered neuraminidase inhibitor zanamivir via inhalation to diabetic mice and in a human trial (NCT04867707).

Main Results:

• T2D subjects exhibited higher plasma neuraminidase activity, lower nitrite, and diminished FMD compared to controls.
• Neuraminidase exposure reduced FMD and glycocalyx presence in mouse arteries and endothelial cells.
• Zanamivir improved FMD and glycocalyx in mice but not in humans due to insufficient plasma concentrations.

Conclusions:

• Neuraminidase is a key mediator of endothelial dysfunction in T2D.
• Neuraminidase inhibition shows potential for treating T2D endothelial dysfunction.
• Current inhaled zanamivir dosage is insufficient for therapeutic benefit in humans.