Mitochondria Oxidative Stress and Vascular Health Study

Overview

Cardiovascular diseases (CVDs) are the number one cause of death in America and most of the post-industrial world. Hypertension is a leading risk factor for CVDs including stroke, myocardial infarction, and heart failure. Black Americans suffer from the highest rates of hypertension of any racial/ethnic group in America, among the highest in the world. There are also well-documented racial disparities in vascular dysfunction (e.g., endothelial dysfunction, arterial stiffening). Thus, racial disparities in hypertension and vascular dysfunction exacerbate the burden of CVDs, with Black Americans being 30% more likely to die from CVD than any other race in the US. It is established that mitochondrial dysfunction contributes to vascular dysfunction. However, there is a knowledge gap regarding whether targeting mitochondrial dysfunction attenuates oxidative stress, vascular dysfunction, and CVD risk among Black adults at heightened CVD risk. Thus, the investigators will conduct an 8-week trial with the mitochondrial antioxidant MitoQ in middle-aged and older Black and non-Black adults. Our overarching 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. Importantly, the investigators will also assess social determinants of health (e.g., income, neighborhood disadvantage, discrimination) and health behaviors (e.g., diet, physical activity) and uncover their role in oxidative stress, vascular function, and BP Regarding methodology, the investigators will perform blood draws, vascular testing, preceding and following an 8-week, 20mg daily consumption of MitoQ and placebo. The investigators will also measure urine biomarkers of kidney function and blood pressure in adults (45-75 years old).

Hypertension develops earlier in life, is more challenging to control, and is associated with greater rates of morbidity, such as end-organ damage (e.g., kidneys) in Black compared to White adults. Recently published data from the Coronary Artery Risk Development in Young Adults (CARDIA) study5 demonstrate that the cumulative incidence of hypertension by age 55 was 76% in Black adults (both males and females), 55% in White males, and 40% in White females and that racial differences in blood pressure (BP) started to emerge as early as the third decade of life. Data from Bogalusa Heart Study suggest that Black individuals have higher BP levels as early as childhood. Black Americans' hypertension rates exceed any other race/ethnic group (not just non-Hispanic White) in America. Black Americans also tend to have worse BP than foreign-born Black adults, indicating a role of socioeconomic factors. The AHA has projected that between 2010 and 2030, direct medical costs of cardiovascular diseases (CVDs) are projected to triple, from $273 billion to $818 billion. Moreover, recent projections demonstrate that the annual costs of health disparities in preventable chronic diseases will increase to $50.1 billion by 2050. Given the alarming public health and economic consequences of hypertension and CVDs, addressing the issue of racial disparities in hypertension to reduce the burden of CVDs is critical. A key contributor to disparities in hypertension and CVD is vascular dysfunction. Several studies have demonstrated racial disparities in endothelial function, arterial stiffness, and autonomic control of BP including exaggerated BP responses to sympathoexcitatory stimuli, such as exercise. However, the underlying mechanisms for the racial difference in vascular dysfunction are still unknown. Excess oxidative stress (i.e., ROS) contributes to racial differences in endothelial function. Black males exhibit greater resting PBMC-derived ROS production which could contribute to increased systemic oxidative stress. Multiple publications also demonstrate that excess ROS contributes to microvascular dysfunction in young non-Hispanic Black compared to non-Hispanic White adults. NADPH oxidase and xanthine oxidase inhibition did not fully attenuate the racial disparity in microvascular function, suggesting that an alternative source of ROS, such as the mitochondria, may play a role in racial disparities in endothelial function. Further, there are data indicating reduced mitochondrial respiration in tissue and cells from Black adults. Recent data from preclinical models and patients with hypertension suggest that depletion of SIRT3 leads to hyperacetylation (i.e., inactivation) of the mitochondrial antioxidant SOD2, which reduces endogenous antioxidant capacity, thus contributing to excessive oxidative stress and vascular dysfunction. Importantly, these findings have also been extended to PBMCs. However, the consideration of this SIRT3" SOD2 inactivation"excess mitochondrial ROS milieu has not been considered in the context of racial disparities in vascular dysfunction and BP regulation. MitoQ (Antipodean Pharmaceuticals) is a dietary supplement produced by covalently bonding ubiquinone, an endogenous mitochondrial antioxidant, and component of the electron transport chain, to a triphenylphosphonium cation to target mitochondria. Over 350 publications including multiple phase II trials have used MitoQ. Rodent findings exhibit that MitoQ accumulates in the vasculature to reduce both circulating and local (i.e., aorta homogenate) ROS. A prior human study that assigned older (60-79 yrs old) adults with impaired endothelial function to six weeks of oral MitoQ supplementation (20 mg/day) demonstrated a 42% improvement in endothelial function in a predominately White cohort. While MitoQ and SOD2 act through different mechanisms, both antioxidants act to reduce mitochondrial-derived oxidative stress. Thus, the investigators are seeking to leverage MitoQ which is commercially available, safe, and has a record of efficacy, to reduce mitochondrial ROS in Black adults, who the investigators hypothesize have reduced endogenous antioxidant activity via the SIRT3 SOD2 inactivation excess mitochondrial ROS milieu.