Abstract 11602: Direct Evidence That Vascular Endothelial Protection Leads to aa Reduction of Heart Failure

Abstract

Introduction: Heart failure (HF) induces endothelial dysfunction, and especially decreases nitric oxide (NO) production, but the direct link between endothelial dysfunction and aggravation of HF is unknown. We previously reported a new treatment of endothelial dysfunction, based on inhibition of protein tyrosine phosphatase 1B (PTP1B), which both increases NO production and reduces cardiac dysfunction in HF. However the exact role of endothelial PTP1B in these effects is unknown. Hypothesis: Specific endothelial deletion of PTP1B reduces HF by limiting endothelial dysfunction Methods: Endothelial deletion of PTP1B was obtained by crossing LoxP-PTP1B mice with mice expressing Cre recombinase under the control of the endothelial promoter Tie2. Since this Tie2-Cre approach is known to also induce gene extinction in hematopoietic cells, Tie2Cre(+)PTP1Bf/f mice were also lethally irradiated and reinjected with bone marrow from wild type (WT; CD45.1) mice, in order to obtain a specific deletion of endothelial PTP1B (endoPTP1B-/- mice). All mice were then subjected to 4 months of myocardial infarction (MI) in order to induce HF, or to sham surgery Results: Vascular function evaluated ex vivo in mesenteric arteries (arteriograph) showed that in WT mice, HF markedly impaired endothelium-dependent, flow-mediated dilatation (sham: 40±4%; HF: 5±5; p<0.001). This HF-induced endothelial dysfunction was less marked in Tie2Cre(+)PTP1Bf/f (MI: 30±5; p<0.001 vs. WT) and in endoPTP1B-/- mice (35±6%). This improved response in endoPTP1B-/- mice were abolished by a NO-synthase inhibitor, suggesting a restored NO production. Evaluation of cardiac function by echocardiography showed that in WT, MI decreased left ventricular fractional shortening (sham: 49±2; HF: 12±1%; p<0.001) and which was improved in Tie2Cre(+)PTP1Bf/f (26±1%; p<0.01 vs. WT), and in endoPTP1B-/- mice (29±1%; p<0.01 vs. WT). In parallel, endothelial PTP1B deficiency was associated with an increased survival. Conclusions: Endothelial PTP1B deficiency induced an improvement of endothelial function but especially improved cardiac function. These results provide a direct demonstration of the beneficial effect of endothelial protection in HF.