Aims Endothelial dysfunction (ED) and red blood cell distribution width (RDW) are both prognostic factors in heart failure (HF), but the relationship between them is not clear. In this study, we used a unique mouse model of chronic HF driven by cardiomyocyte-specific overexpression of activated Gαq protein (Tgαq*44 mice) to characterize the relationship between the development of peripheral ED and the occurrence of structural nanomechanical and biochemical changes in red blood cells (RBCs). Methods and results Systemic ED was detected in vivo in 8-month-old Tgαq*44 mice, as evidenced by impaired acetylcholine-induced vasodilation in the aorta and increased endothelial permeability in the brachiocephalic artery. ED in the aorta was associated with impaired nitric oxide (NO) production in the aorta and diminished systemic NO bioavailability. ED in the aorta was also characterized by increased superoxide and eicosanoid production. In 4- to 6-month-old Tgαq*44 mice, RBC size and membrane composition displayed alterations that did not result in significant changes in their nanomechanical and functional properties. However, 8-month-old Tgαq*44 mice presented greatly accentuated structural and size changes and increased RBC stiffness. In 12-month-old Tgαq*44 mice, the erythropathy was featured by severely altered RBC shape and elasticity, increased RDW, impaired RBC deformability, and increased oxidative stress (gluthatione (GSH)/glutathione disulfide (GSSG) ratio). Moreover, RBCs taken from 12-month-old Tgαq*44 mice, but not from 12-month-old FVB mice, coincubated with aortic rings from FVB mice, induced impaired endothelium-dependent vasodilation and this effect was partially reversed by an arginase inhibitor [2(S)-amino-6-boronohexanoic acid]. Conclusion In the Tgαq*44 murine model of HF, systemic ED accelerates erythropathy and, conversely, erythropathy may contribute to ED. These results suggest that erythropathy may be regarded as a marker and a mediator of systemic ED in HF. RBC arginase and possibly other RBC-mediated mechanisms may represent novel therapeutic targets for systemic ED in HF.

中文翻译：

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慢性心力衰竭小鼠模型中全身内皮功能障碍与红细胞功能改变的时间关系

目的 内皮功能障碍（ED）和红细胞分布宽度（RDW）均是心力衰竭（HF）的预后因素，但两者之间的关系尚不明确。在这项研究中，我们使用了一种由心肌细胞特异性过表达活化 Gαq 蛋白（Tgαq*44 小鼠）驱动的独特慢性 HF 小鼠模型，以表征外周 ED 的发展与红色结构纳米力学和生化变化的发生之间的关系血细胞（红细胞）。方法和结果 在 8 个月大的 Tgαq*44 小鼠体内检测到系统性 ED，这可以通过乙酰胆碱诱导的主动脉血管扩张受损和头臂动脉内皮通透性增加来证明。主动脉中的 ED 与主动脉中一氧化氮 (NO) 生成受损和全身 NO 生物利用度降低有关。主动脉中的 ED 的特征还在于超氧化物和类花生酸的产生增加。在 4 至 6 个月大的 Tgαq*44 小鼠中，RBC 大小和膜组成显示出变化，但并未导致其纳米力学和功能特性发生显着变化。然而，8 个月大的 Tgαq*44 小鼠表现出明显的结构和大小变化以及红细胞硬度增加。在 12 个月大的 Tgαq*44 小鼠中，红细胞病的特征是红细胞形状和弹性严重改变、RDW 增加、红细胞变形能力受损以及氧化应激增加（谷胱甘肽 (GSH)/谷胱甘肽二硫化物 (GSSG) 比率）。此外，红细胞取自 12 个月大的 Tgαq*44 小鼠，而不是取自 12 个月大的 FVB 小鼠，与 FVB 小鼠的主动脉环共同培养，诱导受损的内皮依赖性血管舒张，这种作用被精氨酸酶抑制剂 [2(S)-amino-6-boronohexanoic acid] 部分逆转。结论 在 Tgαq*44 小鼠 HF 模型中，全身性 ED 加速红细胞病变，相反，红细胞病变可能促进 ED。这些结果表明，红细胞病可被视为 HF 全身性 ED 的标志物和介质。RBC 精氨酸酶和可能的其他 RBC 介导的机制可能代表 HF 全身性 ED 的新治疗靶点。