Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes, France.
Oxid Med Cell Longev. 2022 May 18;2022:7377877. doi: 10.1155/2022/7377877. eCollection 2022.
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 -adrenoreceptor (Tg ) 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 Tg 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 O production. Vascular reactivity was altered as early as 15 weeks of age in response to isoproterenol in Tg aortas and mesenteric arteries. NOS1 (neuronal NOS) expression was higher in the Tg aorta at 30 and 45 weeks of age (30 weeks: WT: 1.00 ± 0.21; Tg : 6.08 ± 2.30; 45 weeks: WT: 1.00 ± 0.12; Tg : 1.55 ± 0.17; < 0.05). Interestingly, the endothelial NOS (NOS3) monomer form is increased in Tg rats at 45 weeks of age (ratio NOS3 dimer/NOS3 monomer; WT: 1.00 ± 0.37; Tg : 0.13 ± 0.05; < 0.05). Aortic NO production was increased by NOS2 (inducible NOS) at 15 weeks of age in Tg rats (+52% vs. WT). Aortic O production was increased in Tg rats at 30 and 45 weeks of age (+75% and+76%, respectively, vs. WT, < 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.
50%的心力衰竭患者射血分数保留（HFpEF）。许多研究已经探讨了 HFpEF 的病理生理机制，并表明内皮功能障碍在 HFpEF 中起着重要作用。然而，尚无研究回答内皮功能障碍是 HFpEF 的原因还是后果。最近，我们已经表明，在大鼠中过表达人β-肾上腺素能受体（Tg）会导致随着年龄的增长舒张功能障碍缓慢发展。本研究旨在阐明内皮功能障碍在 HFpEF 发展中的作用。为此，我们研究了 15 周、30 周和 45 周龄的野生型（WT）和 Tg 大鼠的内皮和心脏功能。通过 Western blot 评估主动脉中一氧化氮合酶（NOS）同工型的表达。最后，在主动脉上进行电子顺磁共振测量，以评估 NO 和 O 的产生。在 Tg 大鼠的主动脉和肠系膜动脉中，早在 15 周龄时，异丙肾上腺素就改变了血管反应性。在 30 周和 45 周龄时，Tg 主动脉中 NOS1（神经元型 NOS）表达更高（30 周：WT：1.00 ± 0.21；Tg：6.08 ± 2.30；45 周：WT：1.00 ± 0.12；Tg：1.55 ± 0.17； < 0.05）。有趣的是，在 45 周龄的 Tg 大鼠中，内皮型 NOS（NOS3）单体形式增加（NOS3 二聚体/NOS3 单体比值；WT：1.00 ± 0.37；Tg：0.13 ± 0.05； < 0.05）。在 Tg 大鼠中，15 周龄时 NOS2（诱导型 NOS）增加了主动脉 NO 的产生（增加 52%比 WT）。在 30 周和 45 周龄时，Tg 大鼠的主动脉 O 产生增加（分别增加 75%和 76%，与 WT 相比，均<0.05）。我们已经表明，内皮功能障碍和氧化应激早在 15 周龄时就已经存在，因此我们得出结论，内皮功能障碍可能是 HFpEF 发展的原因。
