Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ.
Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
J Gen Physiol. 2019 Jan 7;151(1):42-52. doi: 10.1085/jgp.201812259. Epub 2018 Dec 19.
Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by a preserved ejection fraction but increased diastolic stiffness and abnormalities of filling. Although the prevalence of HFpEF is high and continues to rise, no effective therapies exist; however, the diabetic drug metformin has been associated with improved diastolic function in diabetic patients. Here we determine the therapeutic potential of metformin for improving diastolic function in a mouse model with HFpEF-like symptoms. We combine transverse aortic constriction (TAC) surgery with deoxycorticosterone acetate (DOCA) supplementation to obtain a mouse model with increased diastolic stiffness and exercise intolerance. Echocardiography and pressure-volume analysis reveal that providing metformin to TAC/DOCA mice improves diastolic function in the left ventricular (LV) chamber. Muscle mechanics show that metformin lowers passive stiffness of the LV wall muscle. Concomitant with this improvement in diastolic function, metformin-treated TAC/DOCA mice also demonstrate preserved exercise capacity. No metformin effects are seen in sham operated mice. Extraction experiments on skinned ventricular muscle strips show that the metformin-induced reduction of passive stiffness in TAC/DOCA mice is due to an increase in titin compliance. Using phospho-site-specific antibodies, we assay the phosphorylation of titin's PEVK and N2B spring elements. Metformin-treated mice have unaltered PEVK phosphorylation but increased phosphorylation of PKA sites in the N2B element, a change which has previously been shown to lower titin's stiffness. Consistent with this result, experiments with a mouse model deficient in the N2B element reveal that the beneficial effect of metformin on LV chamber and muscle stiffness requires the presence of the N2B element. We conclude that metformin offers therapeutic benefit during HFpEF by lowering titin-based passive stiffness.
射血分数保留的心力衰竭（HFpEF）是一种复杂的综合征，其特征为射血分数正常，但舒张僵硬增加和充盈异常。尽管 HFpEF 的患病率很高且持续上升，但目前尚无有效的治疗方法；然而，糖尿病药物二甲双胍已被证明可改善糖尿病患者的舒张功能。在这里，我们确定二甲双胍在改善具有 HFpEF 样症状的小鼠模型舒张功能方面的治疗潜力。我们将升主动脉缩窄（TAC）手术与去氧皮质酮（DOCA）补充相结合，以获得舒张僵硬增加和运动不耐受的小鼠模型。超声心动图和压力-容积分析显示，向 TAC/DOCA 小鼠提供二甲双胍可改善左心室（LV）腔的舒张功能。肌肉力学表明，二甲双胍降低 LV 壁肌肉的被动僵硬。随着舒张功能的改善，接受二甲双胍治疗的 TAC/DOCA 小鼠的运动能力也得到保留。在假手术小鼠中未观察到二甲双胍的作用。对去皮心室肌条的提取实验表明，二甲双胍在 TAC/DOCA 小鼠中降低被动僵硬是由于肌联蛋白顺应性增加所致。使用磷酸化位点特异性抗体，我们检测了肌联蛋白的 PEVK 和 N2B 弹簧元件的磷酸化。接受二甲双胍治疗的小鼠的 PEVK 磷酸化没有改变，但 N2B 元件中的 PKA 位点磷酸化增加，先前的研究表明这会降低肌联蛋白的刚度。与这一结果一致，使用缺乏 N2B 元件的小鼠模型进行的实验表明，二甲双胍对 LV 腔和肌肉僵硬的有益作用需要 N2B 元件的存在。我们的结论是，二甲双胍通过降低基于肌联蛋白的被动僵硬为 HFpEF 提供治疗益处。
