Arterial Stiffness, Vasodilation
Conditions
Keywords
ER stress, Unfolded protein response, Vascular function, Aging, Obesity, TUDCA
Brief summary
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.
Detailed description
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.
Interventions
DRUGAcetylcholine
Endothelium-dependent vasodilation will be determined via graded intra-arterial infusions of acetylcholine (ACh). Doses of 1, 4, 8, and 16 μg/100ml forearm volume/min will be infused in the brachial artery for 3 minutes each.
DRUGSodium Nitroprusside
Endothelium-independent vasodilation will be determined via graded intra-arterial infusions of sodium nitroprusside (SNP). Doses of 0.25, 0.5, 1, and 2 μg/100ml forearm volume/min will be infused in the brachial artery for 3 minutes each.
DRUGAscorbic Acid
The influence of oxidative stress on arterial stiffness and vasodilation will be assessed by using intravenous ascorbic acid (AA). A single supra-physiological dose of 0.06 g/kg fat-free mass (FFM) will be infused over 20 min followed by a drip infusion of 0.02 g/kg FFM administered over 60 min.
Sponsors
Colorado State University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Masking description
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.
Intervention model description
Participants from each group (young healthy weight, young obese, older healthy weight, older obese) will be studied before and after 8 weeks of tauroursodeoxycholic acid (TUDCA) treatment. Additional older obese participants will be studied before and after 8 weeks of a placebo treatment.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* 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)
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Endothelial cell inflammatory marker IL-6 | Change in baseline endothelial IL-6 at 8 weeks | Protein expression of interleukin-6 (IL-6) |
| Endothelial cell ER stress marker IRE1α | 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 CHOP | Change in baseline endothelial CHOP at 8 weeks | Protein expression of CCAAT-enhancer-binding protein homologous protein (CHOP) |
| Endothelial cell ER stress marker GRP78 | Change in baseline endothelial GRP78 at 8 weeks | Protein expression of glucose-regulated protein 78 (GRP78) |
| Endothelial cell ER stress marker GADD34 | Change in baseline endothelial GADD34 at 8 weeks | Protein expression of growth arrest and DNA damage-inducible 34 (GADD34) |
| Endothelial cell oxidative stress marker p47phox | Change in baseline endothelial p47phox at 8 weeks | Protein expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47phox |
| Endothelial cell oxidative stress marker NT | Change in baseline endothelial NT at 8 weeks | Protein expression of nitrotyrosine (NT) |
| Endothelial cell oxidative stress marker MnSOD | Change in baseline endothelial MnSOD at 8 weeks | Protein expression of manganese superoxide dismutase (MnSOD) |
| Endothelial cell oxidative stress marker CuZnSOD | Change in baseline endothelial CuZnSOD at 8 weeks | Protein expression of copper-zinc SOD (CuZnSOD) |
| Endothelial cell inflammatory marker IκBα | Change in baseline endothelial IκBα at 8 weeks | Protein expression of phosphorylated inhibitor of kappa B (IκBα) |
| Endothelial cell inflammatory marker TNFα | Change in baseline endothelial TNFα at 8 weeks | Protein expression of tumor necrosis factor-alpha (TNFα) |
| Endothelium-dependent vasodilation | Change in baseline vasodilation at 8 weeks | Blood flow response to increasing doses of acetycholine |
| Endothelial cell inflammatory marker p65 | Change in baseline endothelial p65 at 8 weeks | Protein expression of nuclear factor kappa B phosphorylated p65 subunit |
| Endothelium-independent vasodilation | Change in baseline vasodilation at 8 weeks | Blood flow response to increasing doses of sodium nitroprusside |
| Aortic stiffness | Change in baseline pulse-wave velocity at 8 weeks | Carotid-femoral pulse-wave velocity |
| Endothelial cell ER stress marker ATF6 | Change in baseline endothelial ATF6 at 8 weeks | Protein expression of activating transcription factor 6 (ATF6) |
| Endothelial cell ER stress marker PERK | Change in baseline endothelial PERK at 8 weeks | Protein expression of RNA-dependent protein kinase- like ER eukaryotic initiation factor-2α kinase (PERK) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Circulating TNFα | Change in baseline TNFα at 8 weeks | Blood levels of tumor necrosis factor-alpha (TNFα) |
| Circulating triglycerides | Change in baseline triglycerides at 8 weeks | Blood levels of triglycerides |
| Circulating CRP | Change in baseline CRP at 8 weeks | Blood levels of C-reactive protein (CRP) |
| Circulating IL-6 | Change in baseline IL-6 at 8 weeks | Blood levels of interleukin (IL)-6 |
| Circulating IL-18 | Change in baseline IL-18 at 8 weeks | Blood levels of interleukin (IL)-18 |
| Circulating IL-10 | Change in baseline IL-10 at 8 weeks | Blood levels of interleukin (IL)-10 |
| Circulating glucose | Change in baseline blood glucose at 8 weeks | Blood glucose |
| Circulating insulin | Change in baseline insulin at 8 weeks | Blood levels of insulin |
| Circulating cholesterol | Change in baseline total cholesterol, LDL cholesterol, and HDL cholesterol at 8 weeks | Blood levels of total cholesterol, LDL cholesterol, and HDL cholesterol |
| Circulating IL-1β | Change in baseline IL-1β at 8 weeks | Blood levels of interleukin (IL)-1 beta (β) |
Countries
United States
Outcome results
None listed