4-hydroxy-2-nonenal in mitochondrial DNA damage and contractile dysfunction in diabetic heart: a role for aldehyde dehydrogenase 2

4-羟基-2-壬烯醛在糖尿病心脏线粒体 DNA 损伤和收缩功能障碍中的作用：乙醛脱氢酶 2 的作用

基本信息

批准号：
9921470
负责人：
Suresh Selvaraj Palaniyandi
金额：
$ 37.78万
依托单位：
HENRY FORD HEALTH SYSTEM
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：
2018-09-01 至 2022-05-31
项目状态：
已结题

项目摘要

Project Abstract: Diabetes mellitus (DM) afflicts 26 million people in the US. Around 65% of these diabetic patients die of cardiovascular complications. We and others have found that DM increases reactive oxygen species (ROS)- mediated aldehydes like 4-hydroxy-2-nonenal (4HNE) levels. 4HNE forms covalent bonds with macromolecules known as adducts, which lead to cellular damage and decreased cardiac function. Aldehyde dehydrogenase (ALDH2) is a cardiac mitochondrial enzyme that detoxifies 4HNE greatly in the heart. We and others have reported that in streptozotocin-induced hyperglycemic models increase in 4HNE protein adducts and decrease in myocardial ALDH2 activity correlate with cardiomyopathy. Although we think this causes cardiac dysfunction, the exact mechanism is unclear. However, most diabetic patients have type-2 DM. Thus, it is imperative to investigate whether increased mitochondrial 4HNE and lower ALDH2 activity in the cardiomyocytes contribute to cardiac dysfunction in type-2 DM models. We recently demonstrated that high glucose stress or 4HNE administration decreased mitochondrial respiration with increased mitochondrial DNA (mtDNA) damage in cultured cardiomyocytes. In our preliminary study using type-2 diabetic mouse heart, we found an increase in mitochondrial levels of 8-hydroxyguanine (8OHG), an oxidized mtDNA product, which is primarily repaired by 8- oxoguanine glycosylase (OGG)-1. Next, we found increased 4HNE adduct formation on OGG-1 and reduced cardiac OGG-1 levels. These data suggest that 4HNE adduction on OGG-1 reduces its level and activity thereby raising the unmetabolized 8OHG level. Thus, we postulate that 4HNE-mediated mtDNA damage is part of the mechanism by which lower ALDH2 causes mitochondrial respiratory dysfunction and thus cardiac contractile dysfunction. To test our idea, we will use a high-fat diet induced type-2 DM model in wild type C57BL/6 and ALDH2*2 mutant mice. This mutation mimics East Asians with the E487K variant (ALDH2*2), which exhibits lower ALDH2 activity. We will overexpress ALDH2 and OGG-1 genes in the myocardium in situ or treat our diabetic mice with Alda-1, the only specific drug available to improve the catalytic activity of both wild type and mutant ALDH2. We propose following two specific aims: Aim 1. To determine whether increased 4HNE adduction on mtOGG-1 causes mtDNA damage, poor mitochondrial respiration, and impaired cardiomyocyte contractility in type-2 DM. Aim 2. To determine whether decreasing 4HNE-mediated mtDNA damage after the onset of cardiac dysfunction in type2-DM attenuates pathogenesis of cardiomyopathy. This study will identify a novel role of ALDH2 in type-2 DM mediated cardiac dysfunction and establish that ALDH2 could be a therapeutic target for restoring cardiac function in type-2 diabetic patients.

项目摘要：糖尿病（DM）在美国遭受了2600万人的困扰。这些糖尿病患者中约有65％死于心血管并发症。我们和其他人发现DM增加了活性氧（ROS） - 4-羟基-2-非纳尔（4HNE）水平等介导的醛。 4HNE形成与大分子的共价键被称为加合物，导致细胞损伤和心脏功能降低。醛脱氢酶（ALDH2）是一种心脏线粒体酶，在心脏中大大排毒4HNE。我们和其他人有报道说，在链蛋白酶诱导的高血糖模型中，4HNE蛋白加合物增加并减少在心肌中，ALDH2活性与心肌病有关。尽管我们认为这会引起心脏功能障碍，但确切的机制尚不清楚。但是，大多数糖尿病患者都有2型DM。因此，必须研究心肌细胞中线粒体4HNE和降低ALDH2活性是否有助于在2型DM模型中进行心脏功能障碍。我们最近证明了高葡萄糖应激或4HNE 通过增加线粒体DNA（mtDNA）损伤的线粒体呼吸降低培养的心肌细胞。在使用2型糖尿病小鼠心脏的初步研究中，我们发现 8-羟基鸟氨酸（8OHG）的线粒体水平，一种氧化的mtDNA产物，主要由8--修复氧气糖基酶（OGG）-1。接下来，我们发现在OGG-1上增加了4HNE加合物的形成并减少了心脏OGG-1水平。这些数据表明，OGG-1上的4HNE内收质量降低了其水平和活动提高未代谢的8OHG水平。因此，我们假设4Hne介导的mtDNA损伤是较低ALDH2引起线粒体呼吸功能障碍的机制，从而导致心脏收缩功能障碍。为了测试我们的想法，我们将在野生型C57BL/6中使用高脂饮食诱导的2型DM模型和 ALDH2*2突变小鼠。这种突变与E487K变体（Aldh2*2）模仿东亚人降低ALDH2活性。我们将在心肌中过表达ALDH2和OGG-1基因或治疗我们的 ALDA-1的糖尿病小鼠，ALDA-1，这是唯一可用于改善野生型和催化活性的特异性药物突变aldh2。我们提出以下两个具体目标：目标1。确定MTOGG-1上的4HNE收缩是否会导致mtDNA损害，差。线粒体呼吸和2型DM中的心肌细胞收缩性受损。目标2。确定心脏发作后是否减少4HNE介导的mtDNA损伤 Type2-DM的功能障碍会减弱心肌病的发病机理。这项研究将确定ALDH2在2型DM介导的心脏功能障碍中的新作用，并确定这一点 ALDH2可能是恢复2型糖尿病患者心脏功能的治疗靶点。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Correction: Type-2 diabetic aldehyde dehydrogenase 2 mutant mice (ALDH 2*2) exhibiting heart failure with preserved ejection fraction phenotype can be determined by exercise stress echocardiography.

DOI：
10.1371/journal.pone.0203581
发表时间：
2018
期刊：
PloS one
影响因子：
3.7
作者：
Pan G;Munukutla S;Kar A;Gardinier J;Thandavarayan RA;Palaniyandi SS
通讯作者：
Palaniyandi SS

3'UTR shortening of profibrotic genes and reversibility of fibrosis in patients with end-stage right ventricular failure.

DOI：
10.1002/ctm2.1017
发表时间：
2022-09
期刊：
CLINICAL AND TRANSLATIONAL MEDICINE
影响因子：
10.6
作者：
Neupane, Rahul;Cieslik, Katarzyna A.;Youker, Keith;Palaniyandi, Suresh Selvaraj;Guha, Ashrith;Thandavarayan, Rajarajan A.
通讯作者：
Thandavarayan, Rajarajan A.

Type-2 diabetic aldehyde dehydrogenase 2 mutant mice (ALDH 2*2) exhibiting heart failure with preserved ejection fraction phenotype can be determined by exercise stress echocardiography.