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

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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.