Gender-specific Role of ATM in the Heart

ATM 在心脏中的性别特异性作用

基本信息

批准号：
10202058
负责人：
KRISHNA SINGH
金额：
$ 42.32万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-20 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10202058
关键词：
Address Adult Affect Apoptosis Ataxia Telangiectasia Ataxia Telangiectasia Patients Autophagocytosis Award Biogenesis Body fat Cardiac Cardiac Myocytes Carnitine Palmitoyltransferase I Cessation of life Consumption Counseling Cyclic AMP-Dependent Protein Kinases DNA Double Strand Break Data Defect Diet Disease Energy Metabolism Enzymes Estrogens Excision FRAP1 gene Fatty Acids Fatty acid glycerol esters Female Fibrosis Functional disorder Gender General Population Genes Glucose Growth Heart Heart failure Height Hereditary Disease Heterozygote Homeostasis Hormones Hospitalization Impairment Individual Insulin Investigation Knock-out Left Ventricular Function Left ventricular structure Leptin Linoleic Acids Measures Metabolic Mitochondria Morphology Mus Muscle Cells Mutation Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Myocardium Nutritional Organelles PPAR alpha Patients Phosphotransferases Phytanic Acid Play Predisposition Research Risk Role Signal Transduction Testing Therapeutic Ventricular Function Ventricular Remodeling Weight Weight Gain Women&apos s Group acyl-CoA oxidase adiponectin antioxidant enzyme ataxia telangiectasia mutated protein beta-adrenergic receptor cardioprotection catalase etomoxir fatty acid oxidation glucose metabolism glycogen synthase kinase 3 beta heart function improved in vivo innovation insight male mortality peroxisome prevent programs protein expression response saturated fat sugar treatment strategy western diet

项目摘要

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.

ATM中的突变（共济失调性激素突变激酶）基因引起一种被称为共济失调性毛细血管理的疾病（在）。在患者中，喜欢食用高脂肪和糖的饮食。关于体重的增长迟钝患者的女性身高更为突出。大约2％的一般人群携带杂合子 ATM突变。 ATM杂合子11年前由于缺血性心脏病（IHD）而死，而不是非携带者。过氧化物体和线粒体是脂肪酸氧化（FAO）的关键细胞器。使用ATM缺陷（杂合敲除； HKO）小鼠，我们提供了ATM在β-ar刺激中起重要作用的证据和心肌梗死（MI）诱导的心脏重塑，对心室功能，自噬，纤维化影响和凋亡。 ATM缺乏症也与MI后小鼠死亡率增强有关。我们的初步数据在用西方型饮食（WD）喂养的小鼠中显示出有趣的性别特异性差异14周。在女性 HKO小鼠（不在男性中），WD诱导的身体和脂肪体重增加较低，而心脏功能显着与野生型（WT）女性组更好。但是，ATM缺乏对女性的心脏保护作用 MI后1天废除了小鼠。 AMPK的激活（细胞能量稳态的关键调节剂和自噬/果糖）和过氧化氢酶的表达（过氧化物中的主要抗氧化剂）较低，较低 PGC1α的表达（能量代谢和过氧化物体生物发生的关键调节剂），PMP70（标记过氧化物体生物发生），ACOX1（酰基-COA氧化酶1;过氧化物剂量的速率限制酶）和CPT1B （Carnitine Palmitoltransferase 1b;用于线粒体脂肪酸进口的关键酶进口）在 MI后1天的HKO-WD雌性左心室的非肉眼区域。该提议的一个主要目标是了解ATM缺乏症在WD诱导的心肌重塑中的性别特定作用，并在 mi。假设增强心脏的过氧化物体生物发生在女性中起心脏保护作用在MI之前的ATM缺乏症中的小鼠。但是，AMPK活性降低和失调的表达 PGC1α，PMP70和ACOX1损害了葡萄糖的利用率，果糖/自噬和线粒体功能 MI后导致心脏功能障碍加剧。 AIM 1调查，在体内，ATM的性别特定角色在响应WD的心脏中，心脏体内稳态和线粒体稳态中。 AIM 2考试，在体内在WD喂养女性心肌中，在ATM缺乏期间增加葡萄糖利用的有益作用 MI后的小鼠。 AIM 3研究了ATM缺乏改变过氧和线粒体的机制生物发生对脂肪酸的响应，使用从成年WT和HKO女性心肌分离的心肌细胞老鼠。识别影响ATM缺乏期间过氧化物体和线粒体稳态的信号以性别特定的方式可以提供预防/最小化WD和IHD相关的潜在目标心脏的有害变化，尤其是在ATM缺乏症的女性中。此外，研究可能会发现为ATM缺乏症患者治疗IHD和/或营养咨询的治疗策略。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Deficiency of ataxia-telangiectasia mutated kinase attenuates Western-type diet-induced cardiac dysfunction in female mice.

DOI：
10.14814/phy2.15434
发表时间：
2022-09
期刊：
Physiological reports
影响因子：
2.5
作者：
通讯作者：

Deficiency of Ataxia Telangiectasia-mutated Kinase (ATM) Preserves Heart Function by Affecting Cardiac Remodeling in Response to Western-type Diet in Female Mice.

共济失调毛细血管扩张突变激酶（ATM）的缺乏通过影响雌性小鼠对西方饮食的心脏重塑来保护心脏功能。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Ramirez,Paulina;Wingard,Mary;Shook,Paige;Dalal,Suman;Singh,Mahipal;Singh,Krishna
通讯作者：
Singh,Krishna

Macrophages in the Inflammatory Phase following Myocardial Infarction: Role of Exogenous Ubiquitin.