Targeting Endoplasmic Reticulum Stress in Aging- and Obesity-Induced Vascular Dysfunction
试验速览
- 阶段
- 早期 1 期
- 状态
- 终止
- 入组人数
- 17
- 试验地点
- 1
- 主要终点
- Endothelium-independent vasodilation
研究概览
简要总结
Aging and obesity are both risk factors for cardiovascular disease (CVD). One process that links both of these conditions to CVD is vascular dysfunction. Data from animal studies indicate that endoplasmic reticulum (ER) stress may play an important role in the development of endothelial dysfunction in aging and obesity. Therefore, the goal of this study is to investigate the relative contributions of aging and obesity on vascular dysfunction and ER stress. Additionally, this study will determine if taking an oral supplement for 8 weeks will improve vascular dysfunction and ER stress. Results from this study have the potential to identify a safe treatment option for improving vascular function in aging and obese populations.
详细描述
Aging is the primary risk factor for cardiovascular disease (CVD). One critical process that links aging to CVD is the development of vascular dysfunction, characterized by endothelial dysfunction and arterial stiffness. Both endothelial dysfunction and arterial stiffness predict cardiovascular events in older individuals. Aging often coincides with obesity, another independent risk factor for CVD. Although vascular function is well characterized in both aging and obesity, it's unclear how these two conditions interact to modulate vascular function, and whether the combination of aging and obesity has additive or compounding effects on endothelial dysfunction and arterial stiffness.
Currently, it is unknown whether vascular dysfunction is driven by the same underlying cellular mechanisms in aging and obesity. Accumulating data in experimental animals suggest that ER stress may be an important factor in aging- and obesity-related vascular dysfunction. Additionally, middle-aged and older obese adults with endothelial dysfunction display evidence of ER stress within biopsied endothelial cells. In light of these data, the overall goal of this proposal is to test the hypothesis that ER stress is associated with human vascular dysfunction in the settings of aging and obesity, and to determine the efficacy of the chemical chaperone tauroursodeoxycholic acid (TUDCA), an established inhibitor of ER stress, to reduce endothelial cell ER stress and improve vascular function in these at-risk individuals. Results from this study have the potential to identify a novel, safe, and clinically relevant intervention strategy for the treatment of vascular dysfunction in an aging population at high-risk for the development of CVD.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
盲法说明
A study monitor not involved in data collection or analysis will perform masking of both the participant and investigator for the interventions for the older obese participants. These participants will be randomized into placebo or TUDCA treatment groups.
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Young, healthy weight adults (age: 18-35; BMI 18.5-24.9 kg/m2)
- •Young, obese adults (age: 18-35; BMI 30- 39.9 kg/m2)
- •Older, healthy weight adults (age: 60-80; 18.5-24.9 kg/m2)
- •Older, obese adults (age: 60-80; 30-39.9 kg/m2)
排除标准
- •blood pressure >140/90 mmHg
- •triglycerides >500 mg/dL or LDL cholesterol >190 mg/dL
- •current smoking or history of smoking in the last 12 months
- •diagnosed chronic disease including cancer, cardiovascular, diabetes, kidney, liver, and pancreatic disease
- •weight change >3 kg in the past 3 months or actively trying to lose weight
- •>12 alcoholic drinks/week
- •hormone replacement therapy
研究组 & 干预措施
TUDCA
Young and older healthy weight and obese participants will visit the lab for assessment of vascular function prior to the intervention. Aortic stiffness will be evaluated non-invasively using carotid-femoral pulse-wave velocity. A physician will place a catheter in the brachial artery for endothelial cell biopsies and local vasodilator infusions. A venous catheter will also be placed for the systemic ascorbic acid infusion. Aortic stiffness measures and vascular responses to vasodilator infusions will be performed before and after the ascorbic acid infusion. Following the completion of the vascular assessments, participants will receive 1750 mg/day of the dietary supplement tauroursodeoxycholic acid (TUDCA) for 8 weeks. Participants will return to the lab after the 8 week intervention and the vascular assessments described above will be repeated.
干预措施: Acetylcholine (Drug)
TUDCA
Young and older healthy weight and obese participants will visit the lab for assessment of vascular function prior to the intervention. Aortic stiffness will be evaluated non-invasively using carotid-femoral pulse-wave velocity. A physician will place a catheter in the brachial artery for endothelial cell biopsies and local vasodilator infusions. A venous catheter will also be placed for the systemic ascorbic acid infusion. Aortic stiffness measures and vascular responses to vasodilator infusions will be performed before and after the ascorbic acid infusion. Following the completion of the vascular assessments, participants will receive 1750 mg/day of the dietary supplement tauroursodeoxycholic acid (TUDCA) for 8 weeks. Participants will return to the lab after the 8 week intervention and the vascular assessments described above will be repeated.
干预措施: Sodium Nitroprusside (Drug)
TUDCA
Young and older healthy weight and obese participants will visit the lab for assessment of vascular function prior to the intervention. Aortic stiffness will be evaluated non-invasively using carotid-femoral pulse-wave velocity. A physician will place a catheter in the brachial artery for endothelial cell biopsies and local vasodilator infusions. A venous catheter will also be placed for the systemic ascorbic acid infusion. Aortic stiffness measures and vascular responses to vasodilator infusions will be performed before and after the ascorbic acid infusion. Following the completion of the vascular assessments, participants will receive 1750 mg/day of the dietary supplement tauroursodeoxycholic acid (TUDCA) for 8 weeks. Participants will return to the lab after the 8 week intervention and the vascular assessments described above will be repeated.
干预措施: Ascorbic Acid (Drug)
Placebo
Older obese participants will visit the lab for assessment of vascular function prior to the intervention. Aortic stiffness will be evaluated non-invasively using carotid-femoral pulse-wave velocity. A physician will place a catheter in the brachial artery for endothelial cell biopsies and local vasodilator infusions. A venous catheter will also be placed for the systemic ascorbic acid infusion. Aortic stiffness measures and vascular responses to vasodilator infusions will be performed before and after the ascorbic acid infusion. Following the completion of the vascular assessments, participants will receive oral capsules containing a placebo treatment for 8 weeks. Participants will return to the lab after the 8 week intervention and the vascular assessments described above will be repeated.
干预措施: Acetylcholine (Drug)
Placebo
Older obese participants will visit the lab for assessment of vascular function prior to the intervention. Aortic stiffness will be evaluated non-invasively using carotid-femoral pulse-wave velocity. A physician will place a catheter in the brachial artery for endothelial cell biopsies and local vasodilator infusions. A venous catheter will also be placed for the systemic ascorbic acid infusion. Aortic stiffness measures and vascular responses to vasodilator infusions will be performed before and after the ascorbic acid infusion. Following the completion of the vascular assessments, participants will receive oral capsules containing a placebo treatment for 8 weeks. Participants will return to the lab after the 8 week intervention and the vascular assessments described above will be repeated.
干预措施: Sodium Nitroprusside (Drug)
Placebo
Older obese participants will visit the lab for assessment of vascular function prior to the intervention. Aortic stiffness will be evaluated non-invasively using carotid-femoral pulse-wave velocity. A physician will place a catheter in the brachial artery for endothelial cell biopsies and local vasodilator infusions. A venous catheter will also be placed for the systemic ascorbic acid infusion. Aortic stiffness measures and vascular responses to vasodilator infusions will be performed before and after the ascorbic acid infusion. Following the completion of the vascular assessments, participants will receive oral capsules containing a placebo treatment for 8 weeks. Participants will return to the lab after the 8 week intervention and the vascular assessments described above will be repeated.
干预措施: Ascorbic Acid (Drug)
结局指标
主要结局
Endothelium-independent vasodilation
时间窗: Change in baseline vasodilation at 8 weeks
Blood flow response to increasing doses of sodium nitroprusside
Aortic stiffness
时间窗: Change in baseline pulse-wave velocity at 8 weeks
Carotid-femoral pulse-wave velocity
Endothelial cell oxidative stress marker p47phox
时间窗: Change in baseline endothelial p47phox at 8 weeks
Protein expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47phox
Endothelial cell oxidative stress marker MnSOD
时间窗: Change in baseline endothelial MnSOD at 8 weeks
Protein expression of manganese superoxide dismutase (MnSOD)
Endothelial cell oxidative stress marker CuZnSOD
时间窗: Change in baseline endothelial CuZnSOD at 8 weeks
Protein expression of copper-zinc SOD (CuZnSOD)
Endothelium-dependent vasodilation
时间窗: Change in baseline vasodilation at 8 weeks
Blood flow response to increasing doses of acetycholine
Endothelial cell inflammatory marker p65
时间窗: Change in baseline endothelial p65 at 8 weeks
Protein expression of nuclear factor kappa B phosphorylated p65 subunit
Endothelial cell inflammatory marker IL-6
时间窗: Change in baseline endothelial IL-6 at 8 weeks
Protein expression of interleukin-6 (IL-6)
Endothelial cell ER stress marker ATF6
时间窗: Change in baseline endothelial ATF6 at 8 weeks
Protein expression of activating transcription factor 6 (ATF6)
Endothelial cell ER stress marker IRE1α
时间窗: Change in baseline endothelial IRE1α at 8 weeks
Protein expression of inositol-requiring ER-to-nucleus signaling protein 1(IRE1α)
Endothelial cell ER stress marker GRP78
时间窗: Change in baseline endothelial GRP78 at 8 weeks
Protein expression of glucose-regulated protein 78 (GRP78)
Endothelial cell ER stress marker GADD34
时间窗: Change in baseline endothelial GADD34 at 8 weeks
Protein expression of growth arrest and DNA damage-inducible 34 (GADD34)
Endothelial cell oxidative stress marker NT
时间窗: Change in baseline endothelial NT at 8 weeks
Protein expression of nitrotyrosine (NT)
Endothelial cell inflammatory marker IκBα
时间窗: Change in baseline endothelial IκBα at 8 weeks
Protein expression of phosphorylated inhibitor of kappa B (IκBα)
Endothelial cell ER stress marker PERK
时间窗: Change in baseline endothelial PERK at 8 weeks
Protein expression of RNA-dependent protein kinase- like ER eukaryotic initiation factor-2α kinase (PERK)
Endothelial cell ER stress marker CHOP
时间窗: Change in baseline endothelial CHOP at 8 weeks
Protein expression of CCAAT-enhancer-binding protein homologous protein (CHOP)
Endothelial cell inflammatory marker TNFα
时间窗: Change in baseline endothelial TNFα at 8 weeks
Protein expression of tumor necrosis factor-alpha (TNFα)
次要结局
- Circulating CRP(Change in baseline CRP at 8 weeks)
- Circulating triglycerides(Change in baseline triglycerides at 8 weeks)
- Circulating IL-6(Change in baseline IL-6 at 8 weeks)
- Circulating IL-10(Change in baseline IL-10 at 8 weeks)
- Circulating TNFα(Change in baseline TNFα at 8 weeks)
- Circulating insulin(Change in baseline insulin at 8 weeks)
- Circulating IL-1β(Change in baseline IL-1β at 8 weeks)
- Circulating glucose(Change in baseline blood glucose at 8 weeks)
- Circulating cholesterol(Change in baseline total cholesterol, LDL cholesterol, and HDL cholesterol at 8 weeks)
- Circulating IL-18(Change in baseline IL-18 at 8 weeks)