Probing the Role of Mitochondrial Oxidative Stress in Impaired Vascular Function Among Young Adults With Early Life Adversity

Обзор

Adverse childhood experiences (ACEs) represent highly stressful events in the first 18 years of life that include abuse, neglect, and household and community-level dysfunction. Greater exposure to ACEs are associated with greater increases in the risk of cardiovascular diseases and death. Our laboratory has previously observed that vascular function is disrupted in young adults with prior ACE exposure, even though these individuals appear to be healthy clinically (i.e., no classic clinical cardiovascular disease risk factors). There is a need to identify and understand the biological mechanisms underlying these vascular impairments to inform effective interventions to reduce cardiovascular risks the millions of individuals affected by ACEs. The body's response to stress is coordinated across various systems, all of which depend on energy supplied by mitochondria (often referred to as the "powerhouse of cells"). Based on new evidence across multiple physiological systems from our team, our overarching hypothesis is that disruption of mitochondrial function contributes to cardiovascular impairments among young adults with ACEs. Here we propose the initial pilot work necessary to begin to understand these associations, which will directly inform identification of individuals who may be most vulnerable to stress-related cardiovascular risk and the development of interventions to promote cardiovascular-stress resilience. Our aims are to: 1. Determine whether mitochondrial oxidative stress contributes to impaired vascular function among young adults who experienced early life adversity. 2. Determine whether reducing mitochondrial oxidative stress improves the cellular stress and integrated cardiovascular response to laboratory-based psychosocial stress among young adults who experienced early life adversity.

Подробное описание

Adverse childhood experiences (ACEs) represent highly stressful events in the first 18 years of life that include abuse, neglect, and household and community-level dysfunction. ACEs promote cardiovascular morbidity and mortality in a graded, dose-dependent manner1 and are thus a significant, widespread determinant of cardiovascular disease (CVD). In agreement with preclinical evidence,2 we have established that young adults (18-29 y) with prior ACE exposure exhibit impaired vascular endothelial function (VEF)3 as evidenced by reduced flow mediated dilation even in the absence of clinical CVD risk factors. The vascular endothelium is a regulatory organ that plays a critical role in maintaining cardiovascular homeostasis, and our findings indicate that vascular endothelial dysfunction is one of the earliest identifiable pathophysiological mechanisms linking ACE exposure with future CVD. There remains a critical biomedical need to identify and understand the psychobiological mechanisms underlying ACEs-related vascular endothelial dysfunction to inform effective interventions to improve cardiovascular health in the millions of individuals affected by ACEs. The physiologic response to stress is coordinated across various physiological systems, all of which depend on energy supplied at the cellular level by mitochondria. Based on novel evidence across multiple physiological systems from our team, our overarching hypothesis is that dysregulation of mitochondrial function due to chronic stress burden - or mitochondrial allostatic load (MAL) - promotes dysregulation of the physiological stress response which is ultimately transduced to impairments in VEF in young adults with ACEs. Notably, our preliminary evidence also suggests that psychological resilience and executive functions such as cognitive reappraisal may moderate these relations, reducing MAL and preserving VEF in the face of substantial adversity. Here we propose the critical work necessary to understand these associations, which will directly inform identification of individuals who may be most vulnerable to stress-related cardiovascular risk and the development of interventions to promote cardiovascular-stress resilience.

In this study, we will use an acute dose of a mitochondrial targeted antioxidant supplement (MitoQ; or placebo) to experimentally interrogate the role of mitochondrial oxidative stress is associated with improvements in 1) vascular endothelial function and 2) cellular and integrated cardiovascular responses to a standardized laboratory based psychosocial stressor in young adults with Adverse Childhood Experiences.

Participants will report to the laboratory, provide a blood sample and have vascular endothelial function assessed using a specialized test known as flow mediated dilation, consume a single acute dose of MitoQ previously demonstrated to be effective and safe for acutely decreasing mitochondrial oxidative stress in humans OR placebo, and then have vascular endothelial function measured again. Next, participants will provide another blood sample before undergoing a standardized and commonly used laboratory psychosocial stress test known, before providing additional blood samples after test completion.

1\. Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, Koss MP, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults: The adverse childhood experiences (ace) study. American Journal of Preventive Medicine. 1998;14:245-58. 2. Su S, Jimenez MP, Roberts CT, Loucks EB. The role of adverse childhood experiences in cardiovascular disease risk: A review with emphasis on plausible mechanisms. Curr Cardiol Rep. 2015;17:88. PMC4941633 3. Jenkins NDM, Rogers EM, Banks NF, Tomko PM, Sciarrillo CM, Emerson SR, Taylor A, et al. Childhood psychosocial stress is linked with impaired vascular endothelial function, lower sirt1, and oxidative stress in young adulthood. Am J Physiol Heart Circ Physiol. 2021;321:H532-H41. PMC8461842

Вмешательства

• Пищевая добавка Mitoquinone mesylate (MitoQ)
  Participants will consume a single 160 mg dose of mitoquinone mesylate, provided in the form of 6, 20 mg capsules, with water.
• Пищевая добавка Placebo
  Participants will consume a single 160 mg dose of microcrystalline cellulose and tapioca (placebo), provided in 20 mg capsules, with water.

Первичные конечные точки

• Vascular endothelial function [Срок оценки: Prior to supplementation and 60 minutes after supplementation]
• Blood pressure [Срок оценки: 75 minutes after supplementation, during, and for 45 minutes after completion of the Trier Social Stress Test.]
• Endothelial Cell Microparticle Release [Срок оценки: 60 minutes after supplementation and immediately following, 5-10 min, 15-20 min, and 45 min following the Trier Social Stress Test.]
• Cortisol [Срок оценки: 60 minutes after supplementation and immediately following, 5-10 min, 15-20 min, and 45 min following the Trier Social Stress Test.]

Вторичные конечные точки (3)

• Total Peripheral Resistance [Срок оценки: 75 minutes after supplementation, during, and for 45 minutes after completion of the Trier Social Stress Test.]
• Cardiac Output [Срок оценки: 75 minutes after supplementation, during, and for 45 minutes after completion of the Trier Social Stress Test.]
• Growth Differentiation Factor 15 [Срок оценки: 60 minutes after supplementation and immediately following, 5-10 min, 15-20 min, and 45 minutes after completion of the Trier Social Stress Test.]

Критерии участия

Критерии включения

• 18-29 years
• ACE score >=4

Критерии исключения

• Resting arterial blood pressure >140/90 mmHg
• BMI <=17 or >= 35
• Are on a weight-loss diet or involved in a formal weight-loss program or are not intentionally weight stable for 6 months (+/- 5 kg) prior to the study.
• Cardiovascular or metabolic prescription drug use
• Vasoactive antidepressant drug use (SSRIs and clonidine)
• Current heavy alcohol use, as defined as binge drinking on 5 or more days in the last month, or consuming more than 7 (women) or 14 (men) drinks per week in the last month (per NIAAA definition)
• Current or recent (within the last 6 mo.) illicit drug use disorder as indicated by a score of 3 or greater on the Drug Abuse Screening Test (DAST-10)
• Current tobacco or nicotine use
• Vaping
• Regular vigorous (>6 METs) aerobic exercise (>4 bouts/week, >30 min/bout)
• dietary supplementation with antioxidants or habitual use of NSAIDs
• Currently pregnant or breastfeeding

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Фундаментальное исследование

Центры проведения

США · 1 центр

• Integrative Laboratory of Applied Physiology and Lifestyle Medicine — Iowa City

Публикации

• Jenkins NDM, Rogers EM, Banks NF, Tomko PM, Sciarrillo CM, Emerson SR, Taylor A, Teague TK. Childhood psychosocial stress is linked with impaired vascular endothelial function, lower SIRT1, and oxidative stress in young adulthood. Am J Physiol Heart Circ Physiol. 2021 Sep 1;321(3):H532-H541. doi: 10.1152/ajpheart.00123.2021. Epub 2021 Jul 30. PMID 34328346
• Su S, Jimenez MP, Roberts CT, Loucks EB. The role of adverse childhood experiences in cardiovascular disease risk: a review with emphasis on plausible mechanisms. Curr Cardiol Rep. 2015 Oct;17(10):88. doi: 10.1007/s11886-015-0645-1. PMID 26289252
• Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, Koss MP, Marks JS. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med. 1998 May;14(4):245-58. doi: 10.1016/s0749-3797(98)00017-8. PMID 9635069

Идентификаторы

NCT: NCT07244809 · 202504919

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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