Zanamivir infusion improves endothelial function and reduces arterial stiffness in diabetic mice

Abstract

Endothelial dysfunction and arterial stiffening are consistently manifested in type 2 diabetes (T2D) and contribute to the development of cardiovascular disease. Consequently, there is an urgent need to identify novel therapies that improve endothelial function and reduce arterial stiffness in T2D. Endothelial dysfunction is characterized by a reduced capacity of the endothelium to induce vasodilation. Physiologically, this is evident as an impairment in flow-mediated dilation, a process in which the endothelial glycocalyx participates in the mechanosensation and mechanotransduction of shear that leads to the production of the vasodilator nitric oxide. Nitric oxide, in turn, has also been shown to be a potent regulator of vascular wall homeostasis, including arterial stiffness. In T2D, circulating neuraminidase activity is increased and implicated in glycocalyx degradation and endothelial dysfunction. Accordingly, we hypothesized that inhibition of neuraminidase activity would enhance endothelial function and reduce arterial stiffness in T2D. We tested this hypothesis in diabetic db/db mice infused with zanamivir (n=10) or vehicle control (n=10) for 4 weeks via subcutaneously implanted osmotic mini pumps. We chose to use the FDA approved neuraminidase inhibitor zanamivir to increase the translatability of our study. Treatment with zanamivir did not affect body weight or blood pressure. Nonetheless, it improved flow-mediated dilation in isolated mesenteric arteries assessed using pressure myography, with no associated changes in endothelium-independent vasodilation. Zanamivir also reduced stiffness in isolated mesenteric and femoral arteries, as well as aortic stiffness as assessed in vivo via pulse wave velocity and ex vivo via atomic force microscopy. These results indicate that zanamivir is a potential therapeutic to ameliorate vascular dysfunction in T2D. National Institutes of Health grant: R01HL153264 to LM-L and JP This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.