Gender-specific Role of ATM in the Heart

ATM(共济失调毛细血管扩张突变激酶)基因突变导致一种称为共济失调毛细血管扩张的疾病 (At)。AT患者更喜欢吃高脂肪和高糖的饮食。与体重和体重有关的生长迟缓 身高在女性AT患者中更为突出。大约2%的总人口携带杂合子 自动取款机的突变。ATM杂合子比非携带者死于缺血性心脏病(IHD)早11年。 过氧化物酶体和线粒体是脂肪酸氧化的关键细胞器。使用自动柜员机有缺陷 (杂合基因敲除)小鼠，我们提供了ATM在β-AR刺激中发挥重要作用的证据 和心肌梗死(MI)引起的心脏重构对心功能、自噬、纤维化的影响 和细胞凋亡。ATM缺乏也与小鼠心肌梗死后死亡率增加有关。我们的初步数据 在喂食西式饮食(WD)14周的小鼠中，显示出有趣的性别差异。在女性中 HKO小鼠(雄性除外)，WD诱导的体重和脂肪增加较低，而心功能显著 比野生型(WT)女性更好。然而，ATM缺乏对女性的心脏保护作用 心肌梗死后1d处死小鼠。AMPK的激活(细胞能量动态平衡的关键调节因子 自噬/内噬)和过氧化氢酶(过氧化氢酶是过氧化物体中的主要抗氧化酶)的表达较低， 而能量代谢和过氧化酶体生物发生的关键调节因子Pc1α、PMP70(能量代谢和过氧化物酶的标志物)的表达 过氧酶体生物发生)、ACOX1(酰辅酶A氧化酶1；过氧化物型粮农组织中的限速酶)和CPT1B (肉碱棕榈酰转移酶1B；线粒体脂肪酸输入的关键酶)在 HKO-WD女性心肌梗死后1天左室非梗死区。这项提议的一个主要目标是 了解ATM缺乏在WD诱导的心肌重构前后的性别特异性作用 密西西比。据推测，心脏中增强的过氧化物酶体生物生成对女性具有心脏保护作用 小鼠在心肌梗死前ATM缺乏症。然而，AMPK活性降低和表达异常 前列环素α、PMP70和ACOX1损害葡萄糖利用、自噬/自噬和线粒体功能 导致心肌梗死后心功能不全加重。目的1在活体内研究ATM的性别特异性作用 在WD的反应下，心脏中的过氧化物体和线粒体的动态平衡。AIM 2在活体内检查了 喂养WD的雌性雌性在ATM缺乏时提高葡萄糖利用率的有益作用 小鼠心肌梗死后。目的3研究ATM缺乏改变过氧化体和线粒体的机制 成年WT和HKO女性心肌细胞对脂肪酸反应的生物发生 老鼠。ATM缺乏时影响过氧化体和线粒体动态平衡的信号识别 可以为预防/尽量减少与WD和IHD有关的疾病提供潜在的目标 心脏的有害变化，特别是在ATM缺乏的女性。此外，这些研究可能会揭示 治疗IHD的治疗策略和/或为ATM缺乏症患者提供营养咨询。

Mutations in ATM (ataxia telangiectasia mutated kinase) gene cause a disease known as ataxia telangiectasia (AT). AT patients prefer to consume a diet high in fat and sugar. Growth retardation with respect to weight and height is more prominent in female AT patients. Approximately 2% of the general population carries heterozygous ATM mutation. ATM heterozygotes die 11 years earlier due to ischemic heart disease (IHD) than non-carriers. Peroxisomes and mitochondria are the key organelles for fatty acid oxidation (FAO). Using ATM deficient (heterozygous knockout; hKO) mice, we provided evidence that ATM plays an important role in β-AR-stimulated and myocardial infarction (MI)-induced cardiac remodeling with effects on ventricular function, autophagy, fibrosis and apoptosis. ATM deficiency also associated with enhanced mortality in mice post-MI. Our preliminary data show interesting gender-specific differences in mice fed with Western-type diet (WD) for 14 weeks. In female hKO mice (not in males), WD-induced body and fat weight gains were lower, while heart function was significantly better versus the wild-type (WT) female group. However, the cardioprotective effects of ATM deficiency in female mice were abolished 1 day post-MI. Activation of AMPK (key regulator of cellular energy homeostasis and autophagy/pexophagy) and expression of catalase (predominant antioxidant enzyme in peroxisomes) were lower, while expression of PGC1α (key regulator of energy metabolism and peroxisome biogenesis), PMP70 (marker of peroxisome biogenesis), ACOX1 (acyl-CoA oxidase 1; rate-limiting enzyme in peroxisomal FAO) and CPT1B (carnitine palmitoyltransferase 1B; pivotal enzyme for mitochondrial fatty acid import) was dysregulated in the non-infarcted zone of left ventricle of hKO-WD females 1 day post-MI. A major objective of this proposal is to understand the gender-specific role of ATM deficiency in WD-induced myocardial remodeling prior to and post- MI. It is hypothesized that enhanced peroxisome biogenesis in the heart plays a cardioprotective role in female mice during ATM deficiency prior to MI. However, decreased AMPK activity and dysregulated expression of PGC1α, PMP70 and ACOX1 impairs glucose utilization, pexophagy/autophagy and mitochondrial function leading to exacerbated cardiac dysfunction post-MI. Aim 1 investigates, in vivo, the gender-specific role of ATM in peroxisomal and mitochondrial homeostasis in the heart in response to WD. Aim 2 examines, in vivo, the beneficial effects of enhanced glucose utilization during ATM deficiency in the myocardium of WD-fed female mice post-MI. Aim 3 investigates the mechanism by which ATM deficiency alters peroxisomal and mitochondrial biogenesis in response to fatty acids using myocytes isolated from the myocardium of adult WT and hKO female mice. Identification of signals affecting the peroxisomal and mitochondrial homeostasis during ATM deficiency in a gender-specific manner may provide potential targets for preventing/minimizing WD- and IHD-related deleterious changes in the heart, particularly in females with ATM deficiency. In addition, the studies may uncover therapeutic strategies for the treatment of IHD and/or nutritional counseling for individuals with ATM deficiency.