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The Endothelial Dysfunction Could Be a Cause of Heart Failure with Preserved Ejection Fraction Development in a Rat Model
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International audience. 50% of patients with heart failure have a preserved ejection fraction (HFpEF). Numerous studies have investigated the pathophysiological mechanisms of HFpEF and have shown that endothelial dysfunction plays an important role in HFpEF. Yet no studies answered whether endothelial dysfunction could be the cause or is the consequence of HFpEF. Recently, we have shown that the endothelial overexpression of human β3-adrenoreceptor (Tgβ3) in rats leads to the slow development of diastolic dysfunction over ageing. The aim of the study is to decipher the involvement of endothelial dysfunction in the HFpEF development. For that, we investigated endothelial and cardiac function in 15-, 30-, and 45-week-old wild-type (WT) and Tgβ3 rats. The aortic expression of •NO synthase (NOS) isoforms was evaluated by Western blot. Finally, electron paramagnetic resonance measurements were performed on aortas to evaluate •NO and O2•- production. Vascular reactivity was altered as early as 15 weeks of age in response to isoproterenol in Tgβ3 aortas and mesenteric arteries. NOS1 (neuronal NOS) expression was higher in the Tgβ3 aorta at 30 and 45 weeks of age (30 weeks: WT: 1.00 ± 0.21 ; Tgβ3: 6.08 ± 2.30 ; 45 weeks: WT: 1.00 ± 0.12 ; Tgβ3: 1.55 ± 0.17 ; p < 0.05 ). Interestingly, the endothelial NOS (NOS3) monomer form is increased in Tgβ3 rats at 45 weeks of age (ratio NOS3 dimer/NOS3 monomer; WT: 1.00 ± 0.37 ; Tgβ3: 0.13 ± 0.05 ; p < 0.05 ). Aortic •NO production was increased by NOS2 (inducible NOS) at 15 weeks of age in Tgβ3 rats (+52% vs. WT). Aortic O2•- production was increased in Tgβ3 rats at 30 and 45 weeks of age (+75% and+76%, respectively, vs. WT, p < 0.05 ). We have shown that endothelial dysfunction and oxidative stress are present as early as 15 weeks of age and therefore conclude that endothelial dysfunction could be a cause of HFpEF development.
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