Mitochondria Dysfunction as a Contributor to Racial Disparities in Vascular Health and Hypertension

线粒体功能障碍导致血管健康和高血压的种族差异

基本信息

批准号：
10515262
负责人：
Andreas N Kavazis
金额：
$ 43.92万
依托单位：
AUBURN UNIVERSITY AT AUBURN
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10515262
关键词：
Acetylation Address Adult Aging Americas Antioxidants Attenuated Biological Factors Black American Black race Blood Pressure Blood Vessels Cardiovascular Diseases Cause of Death Cells Complex Data Deacetylase Development Diet Discrimination Economic Factors Endothelium Ethnic group Exhibits Female Goals Health Health behavior Heart failure High Prevalence Hour Human Hypertension Impairment In Situ Income Industrialization Knowledge Laboratories Measures Mediating Methods Mitochondria Molecular Biology Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Organ Outcome Oxidative Stress Participant Patients Peripheral Blood Mononuclear Cell Physical activity Physiologic pulse Physiology Population Prevention strategy Production Race Reactive Oxygen Species Reflex action Research Research Personnel Research Project Grants Respiration Rest Role SOD2 gene Sirtuins Source Stroke Students Superoxides Supplementation Testing Tissues Training Translational Research Vascular Diseases arterial stiffness arteriole black men blood pressure elevation brachial artery cardiovascular disorder risk cardiovascular risk factor endothelial dysfunction hypertensive improved indexing innovation male middle age mitochondrial dysfunction neighborhood disadvantage pre-clinical prognostic racial and ethnic racial difference racial disparity sex social factors social health determinants week trial

项目摘要

Cardiovascular diseases (CVDs) are the leading cause of death in America and hypertension is a leading risk factor for CVD. Due to a complex interplay of social, economic, and biological factors, Black Americans suffer from higher hypertension rates than any other racial/ethnic group in America. Black adults are also more likely to exhibit endothelial dysfunction and arterial stiffness, two hallmarks of vascular dysfunction and increased CVD risk. Mitochondria are a major source of vascular oxidative stress, as evidenced by mitochondrial-targeted antioxidants improving vascular function in preclinical and human trials, but these studies have included few, if any, Black adults. Additionally, multiple studies demonstrate reduced mitochondrial respiration in tissue and cells from Black adults, and there are data indicating reduced mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) is associated with increased blood pressure (BP). PBMCs are a major source of vascular oxidative stress and there are documented racial disparities in PBMC-derived oxidative stress. Specifically, Black males exhibit greater resting PBMC-derived superoxide production compared to White males, which could contribute to increased systemic oxidative stress. The source of the reactive oxygen species (ROS) is unclear, but inhibition of non-mitochondrial sources of vascular ROS does not abolish racial disparities in vascular function. Additionally, mitochondrial dysfunction is present in PBMCs from human participants with conditions associated with vascular aging such as type 2 diabetes and hypertension. For example, recent data from PBMCs and arterioles of hypertensive patients suggest that depletion of NAD-dependent deacetylase sirtuin-3 (SIRT3) leads to hyperacetylation (i.e., inactivation) of the mitochondrial antioxidant superoxide dismutase-2 (SOD2) thus contributing to excessive oxidative stress, a hallmark of vascular dysfunction. However, there is a lack of research on the role of mitochondria in contributing to racial disparities in hypertension and vascular dysfunction. Thus, we will conduct an 8-week trial with the mitochondrial antioxidant MitoQ in middle aged and older Black and non-Black adults (n=60, 45-75 years old); and collect additional cross sectional (n=45) in the same population (~equal distribution of race and sex). Our central hypothesis is that mitochondrial dysfunction contributes to heightened oxidative stress, vascular dysfunction and higher BP in Black adults; and that MitoQ will attenuate these racial differences. Regarding our specific hypotheses, our 1st hypothesis is that Black adults will exhibit higher resting and reflex BP and impaired BP dipping and BP measures will be related to PBMC mitochondrial respiration. Our 2nd hypothesis is that Black adults will exhibit reduced endothelial and higher pulse wave velocity; MitoQ will improve vascular function in all races and attenuate racial disparities in vascular function. Our 3rd hypothesis is that PBMCs isolated from Black adults will exhibit reduced mitochondrial respiration and increased ROS production associated with reduced SIRT3 expression and increased SOD2 acetylation.

心血管疾病 (CVD) 是美国人的首要死因，而高血压是主要风险 CVD 的因素。由于社会、经济和生物因素的复杂相互作用，美国黑人遭受苦难高血压发病率高于美国任何其他种族/族裔群体。黑人成年人也更有可能表现出内皮功能障碍和动脉僵硬度，这是血管功能障碍和心血管疾病增加的两个标志风险。线粒体是血管氧化应激的主要来源，线粒体靶向作用证明了这一点在临床前和人体试验中抗氧化剂可以改善血管功能，但这些研究很少包括：任何黑人成年人。此外，多项研究表明组织和细胞中的线粒体呼吸减少来自黑人成年人，有数据表明外周血中线粒体呼吸减少单核细胞 (PBMC) 与血压 (BP) 升高相关。 PBMC 是主要来源血管氧化应激，并且有记录表明 PBMC 衍生的氧化应激存在种族差异。具体来说，与白人男性相比，黑人男性表现出更高的静息 PBMC 衍生的超氧化物产量，这可能会导致全身氧化应激增加。活性氧 (ROS) 的来源尚不清楚，但抑制血管活性氧的非线粒体来源并不能消除种族差异血管功能。此外，患有以下疾病的人类参与者的 PBMC 中存在线粒体功能障碍与血管老化相关的疾病，如 2 型糖尿病和高血压。例如，最近的数据来自高血压患者的 PBMC 和小动脉的结果表明 NAD 依赖性脱乙酰酶的消耗 Sirtuin-3 (SIRT3) 导致线粒体抗氧化剂超氧化物的过度乙酰化（即失活）歧化酶-2 (SOD2) 会导致过度氧化应激，这是血管功能障碍的一个标志。然而，缺乏关于线粒体在高血压种族差异中的作用的研究和血管功能障碍。因此，我们将用线粒体抗氧化剂MitoQ进行为期8周的试验老年人和老年黑人和非黑人成年人（n = 60、45-75 岁）；并收集额外的横截面 (n=45) 在同一人口中（〜种族和性别的平等分布）。我们的中心假设是线粒体功能障碍导致黑人成人氧化应激加剧、血管功能障碍和血压升高；和 MitoQ 将减弱这些种族差异。关于我们的具体假设，我们的第一个假设是黑人成年人将表现出较高的静息血压和反射血压，血压下降受损，血压测量值将与之相关 PBMC 线粒体呼吸。我们的第二个假设是，黑人成年人会表现出内皮细胞减少和较高的脉搏波速度； MitoQ 将改善所有种族的血管功能并缩小种族差异血管功能。我们的第三个假设是，从黑人成人中分离的 PBMC 将表现出线粒体减少呼吸和 ROS 产生增加与 SIRT3 表达减少和 SOD2 增加相关乙酰化。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular predictors of resistance training outcomes in young untrained female adults.

未经训练的年轻女性阻力训练结果的分子预测因素。

DOI：
发表时间：
2023-03-01
期刊：
影响因子：
0
作者：
Smith, Morgan A;Sexton, Casey L;Smith, Kristen A;Osburn, Shelby C;Godwin, Joshua S;Beausejour, Jonathan P;Ruple, Bradley A;Goodlett, Michael D;Edison, Joseph L;Fruge, Andrew D;Robinson, Austin T;Gladden, L Bruce;Young, Kaelin C;Roberts, Micha
通讯作者：
Roberts, Micha

Gut check: Unveiling the influence of acute exercise on the gut microbiota.

肠道检查：揭示急性运动对肠道微生物群的影响。

DOI：
发表时间：
2023-12
期刊：
影响因子：
2.7
作者：
Grosicki, Gregory J;Langan, Sean P;Bagley, James R;Galpin, Andrew J;Garner, Dan;Hampton;Allen, Jacob M;Robinson, Austin T
通讯作者：
Robinson, Austin T