Aims

Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction and is frequent in people with type 2 diabetes mellitus. In diabetic patients, increased levels of the eicosanoid 12-hydroxyeicosatetraenoic acid (12-HETE) are linked to vascular dysfunction. Here, we aimed to identify the importance of 12-HETE in type 2 diabetic patients exhibiting diastolic dysfunction, and mice exhibiting HFpEF and whether targeting 12-HETE is a means to ameliorate HFpEF progression by improving vascular function in diabetes.

Material and methods

Subjects with diagnosed type 2 diabetes mellitus and reported diastolic dysfunction or healthy controls were recruited and 12(S)-HETE levels determined by ELISA. 12(S)-HETE levels were determined in type 2 diabetic, leptin receptor deficient mice (LepR^db/db) and HFpEF verified by echocardiography. Mitochondrial function, endothelial function and capillary density were assessed using Seahorse technique, pressure myography and immunohistochemistry in LepR^db/db or non-diabetic littermate controls. 12/15Lo generation was inhibited using ML351 and 12(S)-HETE action by using the V1-cal peptide.

Key findings

Endothelium-dependent vasodilation and mitochondrial functional capacity both improved in response to either application of ML351 or the V1-cal peptide. Correlating to improved vascular function, mice treated with either pharmacological agent exhibited improved diastolic filling and left ventricular relaxation that correlated with increased myocardial capillary density.

Significance

Our results suggest that 12-HETE may serve as a biomarker indicating endothelial dysfunction and the resulting cardiovascular consequences such as HFpEF in type 2 diabetic patients. Antagonizing 12-HETE is a potent means to causally control HFpEF development and progression in type 2 diabetes by preserving vascular function.

中文翻译：

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通过保留血管功能可改善 2 型糖尿病小鼠射血分数保留的心力衰竭的发展

目标

保留射血分数的心力衰竭( HFpEF )与内皮功能障碍有关，并且在 2 型糖尿病患者中很常见。在糖尿病患者中，类二十烷酸 12-羟基二十碳四烯酸 (12-HETE) 水平升高与血管功能障碍有关。在这里，我们的目的是确定 12-HETE 在表现出舒张功能障碍的 2 型糖尿病患者和表现出 HFpEF 的小鼠中的重要性，以及靶向 12-HETE 是否是通过改善糖尿病血管功能来改善 HFpEF 进展的一种方法。

材料与方法

招募诊断为 2 型糖尿病并报告有舒张功能障碍的受试者或健康对照，并通过 ELISA 测定 12( S )-HETE 水平。^{在 2 型糖尿病、瘦素受体缺陷小鼠 (LepR db/db} )中测定12( S )-HETE 水平，并通过超声心动图验证 HFpEF。^{在 LepR db/db}或非糖尿病同窝对照中，使用 Seahorse 技术、压力肌动描记术和免疫组织化学评估线粒体功能、内皮功能和毛细血管密度。通过使用 V1-cal 肽，利用 ML351 和 12( S )-HETE 作用抑制 12/15Lo 生成。

主要发现

内皮依赖性血管舒张和线粒体功能能力均因应用 ML351 或 V1-cal 肽而得到改善。与血管功能改善相关，用任一药物治疗的小鼠表现出舒张期充盈和左心室舒张改善，这与心肌毛细血管密度增加相关。

意义

我们的结果表明，12-HETE 可以作为指示 2 型糖尿病患者内皮功能障碍以及由此产生的心血管后果（例如 HFpEF）的生物标志物。拮抗 12-HETE 是通过保护血管功能来因果控制 2 型糖尿病 HFpEF 发生和进展的有效方法。