0292: Endothelial protein tyrosine phosphatase 1B deficiency reduces both endothelial and cardiac dysfunction of in a mouse model of aging

Abstract

Aging is associated with an endothelial dysfunction, characterized by a decrease of nitric oxide (NO) production, which is a risk factor of development of cardiovascular diseases. However, the direct link between endothelial dysfunction and aggravation of cardiac function in aging is not established. We reported previously a new potent therapeutic approach of cardiovascular disease, based on inhibition of protein tyrosine phosphatase 1B (PTP1B), which both increases NO production ( via restored PI3K/Akt/eNOS signaling) and reduces cardiac dysfunction in both post-ischemic heart failure and aging, however the exact role of endothelial PTP1B in this setting is unknown. To evaluate the endothelial and cardiac consequences of endothelial PTP1B deficiency (endoPTP1B -/- ) in a mouse model of aging. EndoPTP1B -/- mice were developed by crossing LOX-P PTP1B mice with mice expressing CRE under the control of the endothelial promoter Tie2, or wild-type (WT). The evolution of cardiac function was assessed by echocardiography at different time points and the vascular function was evaluated ex vivo at 24 months. Compared to young (3 month-old), WT mice aged (24 month-old) showed a markedly impaired flow-mediated dilatation of isolated mesenteric arteries (3 months: 40 ± 4%; 24 months: 1 ± 1%; p<0.001), which was improved in endoPTP1B -/- mice (17 ± 3%; p < 0.001 vs. WT 24 months). This restored response in aged endoPTP1B -/- mice was abolished by a NO-synthase inhibitor, suggesting a restored NO production. In WT mice, aging decreased stroke volume (3 months: 0,070 ± 0,002%; 24 months: 0,065 ± 0,005%; p < 0.001) and cardiac output (3 months: 37 ± 1%; 24 months: 29 ± 2%; p < 0.001) and these parameters were improved in endoPTP1B -/- mice (24 months: 0.081 ± 0,011% and 34 ± 2%; respectively, p < 0.05). In aged mice, endoPTP1B deficiency induced an improvement of endothelial function, and also tended to improved cardiac function. These results provide a direct demonstration of the beneficial effect of endothelial protection in aging.