Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee.
Department of Health Sciences, East Tennessee State University, Johnson City, Tennessee.
Am J Physiol Heart Circ Physiol. 2021 Jun 1;320(6):H2324-H2338. doi: 10.1152/ajpheart.00990.2020. Epub 2021 Apr 30.
Ataxia-telangiectasia mutated (ATM) kinase deficiency exacerbates heart dysfunction late after myocardial infarction. Here, we hypothesized that ATM deficiency modulates Western-type diet (WD)-induced cardiac remodeling with an emphasis on functional and biochemical parameters of the heart. Weight gain was assessed in male wild-type (WT) and ATM heterozygous knockout (hKO) mice on weekly basis, whereas cardiac functional and biochemical parameters were measured 14 wk post-WD. hKO-WD mice exhibited rapid body weight gain at and versus WT-WD. WD decreased percent fractional shortening and ejection fraction, and increased end-systolic volumes and diameters to a similar extent in both genotypes. However, WD decreased stroke volume, cardiac output, peak velocity of early ventricular filling, and aortic ejection time and increased isovolumetric relaxation time (IVRT) and Tei index versus WT-NC (normal chow). Conversely, IVRT, isovolumetric contraction time, and Tei index were lower in hKO-WD versus hKO-NC and WT-WD. Myocyte apoptosis and hypertrophy were higher in hKO-WD versus WT-WD. WD increased fibrosis and expression of collagen-1α1, matrix metalloproteinase (MMP)-2, and MMP-9 in WT. WD enhanced AMPK activation, while decreasing mTOR activation in hKO. Akt and IKK-α/β activation, and Bax, PARP-1, and Glut-4 expression were higher in WT-WD versus WT-NC, whereas NF-κB activation and Glut-4 expression were lower in hKO-WD versus hKO-NC. Circulating concentrations of IL-12(p70), eotaxin, IFN-γ, macrophage inflammatory protein (MIP)-1α, and MIP-1β were higher in hKO-WD versus WT-WD. Thus, ATM deficiency accelerates weight gain, induces systolic dysfunction with increased preload, and associates with increased apoptosis, hypertrophy, and inflammation in response to WD. Ataxia-telangiectasia mutated (ATM) kinase deficiency in humans associates with enhanced susceptibility to ischemic heart disease. Here, we provide evidence that ATM deficiency accelerates body weight gain and associates with increased cardiac preload, hypertrophy, and apoptosis in mice fed with Western-type diet (WD). Further investigations of the role of ATM deficiency in WD-induced alterations in function and biochemical parameters of the heart may provide clinically applicable information on treatment and/or nutritional counseling for patients with ATM deficiency.
共济失调毛细血管扩张突变（ATM）激酶缺乏症加剧心肌梗死后的心脏功能障碍。在这里，我们假设 ATM 缺乏症调节西方饮食（WD）诱导的心脏重塑，重点是心脏的功能和生化参数。每周评估雄性野生型（WT）和 ATM 杂合子敲除（hKO）小鼠的体重增加，而 WD 后 14 周测量心脏功能和生化参数。hKO-WD 小鼠在 和 时体重迅速增加，而 WT-WD 则增加。WD 使两种基因型的百分比分段缩短和射血分数降低，而终末期收缩体积和直径增加程度相似。然而，WD 降低了收缩期容积、心输出量、早期心室充盈峰值速度和主动脉射血时间，并增加了等容舒张时间（IVRT）和 Tei 指数，与 WT-NC（正常饮食）相比。相反，IVRT、等容收缩时间和 Tei 指数在 hKO-WD 中低于 hKO-NC 和 WT-WD。hKO-WD 中的心肌细胞凋亡和肥大比 WT-WD 更高。WD 增加了 WT 中的纤维化和胶原-1α1、基质金属蛋白酶（MMP）-2 和 MMP-9 的表达。WD 增强了 hKO 中的 AMPK 激活，同时降低了 mTOR 激活。WT-WD 中的 Akt 和 IKK-α/β激活以及 Bax、PARP-1 和 Glut-4 表达高于 WT-NC，而 hKO-WD 中的 NF-κB 激活和 Glut-4 表达低于 hKO-NC。hKO-WD 中的循环白细胞介素-12（p70）、嗜酸性粒细胞趋化因子、IFN-γ、巨噬细胞炎性蛋白（MIP）-1α 和 MIP-1β 浓度高于 WT-WD。因此，ATM 缺乏加速体重增加，导致收缩功能障碍，前负荷增加，并与 WD 反应中的凋亡、肥大和炎症增加相关。人类的共济失调毛细血管扩张突变（ATM）激酶缺乏症与对缺血性心脏病的易感性增加有关。在这里，我们提供的证据表明，ATM 缺乏加速了体重增加，并与 WD 喂养的小鼠中心脏前负荷增加、肥大和凋亡有关。进一步研究 ATM 缺乏症在 WD 诱导的心脏功能和生化参数变化中的作用，可能为 ATM 缺乏症患者的治疗和/或营养咨询提供临床应用信息。
