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Molecular mechanisms of arrhythmia caused by high-fat diet

高脂饮食引起心律失常的分子机制

基本信息

批准号：
10316166
负责人：
John Pearce Morrow
金额：
$ 40万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10316166
关键词：
Arrhythmia CRISPR/Cas technology Calcium Cardiac Cardiac Myocytes Data Diet Electrophysiology (science)Fatty Acids Frequencies Functional disorder Genes Genetic Genetic Models Genetic Transcription Heart High Fat Diet Human Inner mitochondrial membrane Intake Ion Channel Knockout Mice Link Lipids Methods Mitochondria Modeling Molecular Mus NADPH Oxidase Obesity Olive oil preparation Optics Oxidases Oxidative Stress Pathway interactions Risk Rodent Model Sarcoplasmic Reticulum Serum Signal Transduction TLR4 gene Testing Transgenic Mice Ventricular Ventricular Fibrillation Ventricular Tachycardia Wild Type Mouse acetovanillone calcium uniporter diet-induced obesity experimental study heart rhythm human stem cells in vivo inhibitor lipid metabolism mitochondrial dysfunction monounsaturated fat obese patients prevent saturated fat sudden cardiac death

项目摘要

Obese patients have an increased risk of arrhythmias and twice the risk of sudden cardiac death, which is often caused by ventricular tachycardias (VT). Cardiomyocytes from obese patients have increased lipid content, which is thought to contribute to the pathophysiology of arrhythmia. Furthermore, higher levels of serum fatty acids and higher saturated fat intake in the diet predict sudden cardiac death. This suggests that the arrhythmogenic effects of saturated fat can occur without obesity. An unanswered question is: What are the molecular mechanisms causing arrhythmias during obesity and high-fat diet? The most common electrophysiologic abnormalities found in obese patients are increased frequency of ventricular ectopy and prolongation of the QT interval. We have previously shown that wild type (WT) mice with high-fat diet induced obesity (DIO) have long QT and increased ventricular ectopy, mimicking the abnormalities found in obese humans. Our preliminary data now show that a high saturated fat diet is sufficient to cause ventricular ectopy and prolong the QT interval, and to promote inducibility of VT/VF. Further, mice fed a diet with an equivalent amount of monounsaturated fat from olive oil do not have heart rhythm abnormalities. We discovered that a high saturated fat diet increases cardiac NAPDH oxidase 2 (NOX2) activity, whereas the olive oil high-fat diet does not. The NOX2 inhibitor apocynin, when given during a high saturated fat diet, prevents heart rhythm abnormalities. Additional experiments with isolated cardiac myocytes show that NOX2 is necessary for the oxidative stress and mitochondrial dysfunction caused by saturated fat. We will use both in vivo experiments and cardiomyocytes to determine the pathways linking cardiac lipid metabolism to arrhythmia. Our central hypothesis is that NOX2 activation causes the arrhythmogenic effect of saturated fat by causing sarcoplasmic reticulum calcium leak, which in turn promotes mitochondrial dysfunction. We propose the following independent aims: 1. Determine if NOX2 activation causes arrhythmia during high fat diet, by using genetic gain and loss. 2. Determine how TLR4 signaling contributes to the arrhythmogenic effects of dietary saturated fat. 3. Determine if the mitochondrial abnormalities caused by NOX2 activation promote arrhythmia.

肥胖患者心律失常的风险增加，心脏性猝死的风险增加一倍，常由室性心动过速（VT）引起。肥胖患者的心肌细胞脂质增加内容，这被认为有助于心律失常的病理生理学。此外，更高水平的血清脂肪酸和饮食中较高的饱和脂肪摄入可预测心脏性猝死。这表明饱和脂肪的促肥胖作用可以在没有肥胖的情况下发生。一个没有答案的问题是：肥胖和高脂饮食引起心律失常的分子机制？在肥胖患者中发现的最常见的电生理异常是：心室异位和QT间期延长。我们先前已经表明，野生型（WT）小鼠与高脂饮食诱导的肥胖症（DIO）具有QT延长和心室异位增加，发现于肥胖的人类。我们现在的初步数据显示，高饱和脂肪饮食足以导致延长QT间期，促进VT/VF的诱发。此外，小鼠喂养的饮食从橄榄油中提取等量的单不饱和脂肪，不会出现心律异常。我们发现高饱和脂肪饮食增加心脏NAPDH氧化酶2（NOX 2）活性，而橄榄油高脂肪饮食没有。当在高饱和脂肪饮食期间给予NOX 2抑制剂夹竹桃苷时，防止心律失常。用分离的心肌细胞进行的另外的实验表明，氧化应激和线粒体功能障碍所必需的饱和脂肪。我们将两者都用于体内实验和心肌细胞，以确定心脏脂质代谢与心律不齐我们的中心假设是，NOX 2激活导致饱和脂肪的致癌作用通过引起肌浆网钙泄漏，这反过来又促进线粒体功能障碍。我们提出以下独立目标： 1.通过使用遗传获得和损失确定NOX 2激活是否会导致高脂肪饮食期间的心律失常。 2.确定TLR 4信号传导如何促进膳食饱和脂肪的致癌作用。 3.确定由NOX 2激活引起的线粒体异常是否会促进心律失常。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mechanisms of Chronic Metabolic Stress in Arrhythmias.

DOI：
10.3390/antiox9101012
发表时间：
2020-10-19
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
0
作者：
Gowen BH;Reyes MV;Joseph LC;Morrow JP
通讯作者：
Morrow JP

Sigma non-opioid receptor 1 is a potential therapeutic target for long QT syndrome.

Sigma非阿片受体1是长QT综合征的潜在治疗靶标。

DOI：
10.1038/s44161-021-00016-2
发表时间：
2022-03
期刊：
NATURE CARDIOVASCULAR RESEARCH
影响因子：
0
作者：
Song, LouJin;Bekdash, Ramsey;Morikawa, Kumi;Quejada, Jose R;Klein, Alison D;Aina-Badejo, Danielle;Yoshida, Kazushige;Yamamoto, Hannah E;Chalan, Amy;Yang, Risako;Patel, Achchhe;Sirabella, Dario;Lee, Teresa M;Joseph, Leroy C;Kawano, Fuun;Warren, Junco S;Soni, Rajesh K;Morrow, John P;Yazawa, Masayuki
通讯作者：
Yazawa, Masayuki

Paracardial fat and vitamin A: a mechanism for regulating exercise performance.

心旁脂肪和维生素 A：调节运动表现的机制。

DOI：
10.1172/jci145969
发表时间：
2021
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
Joseph,LeroyC;Morrow,JohnP
通讯作者：
Morrow,JohnP

Combined metabolomic and transcriptomic profiling approaches reveal the cardiac response to high-fat diet.

组合代谢组和转录组学方法方法揭示了对高脂饮食的心脏反应。

DOI：
10.1016/j.isci.2022.104184
发表时间：
2022-05-20
期刊：
ISCIENCE
影响因子：
5.8
作者：
Joseph, Leroy C.;Shi, Jianting;Nguyen, Quynh N.;Pensiero, Victoria;Goulbourne, Chris;Bauer, Robert C.;Zhang, Hanrui;Morrow, John P.
通讯作者：
Morrow, John P.

Metformin Is Associated With a Lower Risk of Atrial Fibrillation and Ventricular Arrhythmias Compared With Sulfonylureas: An Observational Study.