Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome associated with increased myocardial stiffness and cardiac filling abnormalities. Prior studies implicated increased α-tubulin detyrosination, which is catalyzed by the vasohibin enzymes, as a contributor to increased stabilization of the cardiomyocyte microtubule network (MTN) and stiffness in failing human hearts. We explored whether increased MTN detyrosination contributed to impaired diastolic function in the ZSF1 obese rat model of HFpEF and designed a small-molecule vasohibin inhibitor to ablate MTN detyrosination in vivo. Compared with ZSF1 lean and Wistar Kyoto rats, obese rats exhibited increased tubulin detyrosination concomitant with diastolic dysfunction, left atrial enlargement, and cardiac hypertrophy with a preserved left ventricle ejection fraction, consistent with an HFpEF phenotype. Ex vivo myocardial phenotyping assessed cardiomyocyte mechanics and contractility. Vasohibin inhibitor treatment of isolated cardiomyocytes from obese rats resulted in reduced stiffness and faster relaxation. Acute in vivo treatment with vasohibin inhibitor improved diastolic relaxation in ZSF1 obese rats compared with ZSF1 lean and Wistar Kyoto rats. Vasohibin inhibition also improved relaxation in isolated human cardiomyocytes from both failing and nonfailing hearts. Our data suggest the therapeutic potential for vasohibin inhibition to reduce myocardial stiffness and improve relaxation in HFpEF.

中文翻译：

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血管抑制素抑制可改善射血分数保留的心力衰竭大鼠模型的心肌松弛


射血分数保留的心力衰竭（HFpEF）是一种与心肌硬度增加和心脏充盈异常相关的复杂综合征。先前的研究表明，由血管抑制素酶催化的 α-微管蛋白去酪氨酸作用增加，有助于增强心肌细胞微管网络 (MTN) 的稳定性和衰竭人类心脏的硬度。我们探讨了 MTN 去酪氨酸增加是否会导致 ZSF1 肥胖大鼠 HFpEF 模型的舒张功能受损，并设计了一种小分子血管抑制素抑制剂来消除体内 MTN 去酪氨酸。与ZSF1瘦大鼠和Wistar京都大鼠相比，肥胖大鼠表现出微管蛋白脱酪氨酸增加，伴有舒张功能障碍、左心房扩大和心脏肥大，但左心室射血分数保留，与HFpEF表型一致。离体心肌表型评估心肌细胞力学和收缩性。血管抑制素抑制剂对肥胖大鼠分离的心肌细胞进行处理，导致硬度降低和松弛加快。与ZSF1瘦大鼠和Wistar京都大鼠相比，用血管抑制素抑制剂进行急性体内治疗可改善ZSF1肥胖大鼠的舒张舒张。血管抑制素抑制还可以改善来自衰竭心脏和非衰竭心脏的分离的人类心肌细胞的松弛。我们的数据表明血管抑制素抑制具有降低心肌僵硬度和改善 HFpEF 松弛的治疗潜力。