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Trial record 10 of 12 for:    Nicotinamide Adenine Dinucleotide | Aging

Targeting ER Stress in Vascular Dysfunction

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ClinicalTrials.gov Identifier: NCT04001647
Recruitment Status : Recruiting
First Posted : June 28, 2019
Last Update Posted : June 28, 2019
Sponsor:
Information provided by (Responsible Party):
Frank Dinenno, Colorado State University

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.

Condition or disease Intervention/treatment Phase
Vasodilation Arterial Stiffness Drug: Acetylcholine Drug: Sodium Nitroprusside Drug: Ascorbic Acid Early Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Double (Participant, 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.
Primary Purpose: Basic Science
Official Title: Targeting Endoplasmic Reticulum Stress in Aging- and Obesity-Induced Vascular Dysfunction
Actual Study Start Date : June 1, 2019
Estimated Primary Completion Date : June 1, 2022
Estimated Study Completion Date : August 30, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Vitamin C

Arm Intervention/treatment
Experimental: 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.
Drug: Acetylcholine
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.
Other Name: ACh

Drug: Sodium 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.
Other Name: SNP

Drug: Ascorbic 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.
Other Names:
  • AA
  • Vitamin C

Placebo Comparator: 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.
Drug: Acetylcholine
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.
Other Name: ACh

Drug: Sodium 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.
Other Name: SNP

Drug: Ascorbic 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.
Other Names:
  • AA
  • Vitamin C




Primary Outcome Measures :
  1. Endothelium-dependent vasodilation [ Time Frame: Change in baseline vasodilation at 8 weeks ]
    Blood flow response to increasing doses of acetycholine

  2. Endothelium-independent vasodilation [ Time Frame: Change in baseline vasodilation at 8 weeks ]
    Blood flow response to increasing doses of sodium nitroprusside

  3. Aortic stiffness [ Time Frame: Change in baseline pulse-wave velocity at 8 weeks ]
    Carotid-femoral pulse-wave velocity

  4. Endothelial cell ER stress marker ATF6 [ Time Frame: Change in baseline endothelial ATF6 at 8 weeks ]
    Protein expression of activating transcription factor 6 (ATF6)

  5. Endothelial cell ER stress marker PERK [ Time Frame: Change in baseline endothelial PERK at 8 weeks ]
    Protein expression of RNA-dependent protein kinase- like ER eukaryotic initiation factor-2α kinase (PERK)

  6. Endothelial cell ER stress marker IRE1α [ Time Frame: Change in baseline endothelial IRE1α at 8 weeks ]
    Protein expression of inositol-requiring ER-to-nucleus signaling protein 1(IRE1α)

  7. Endothelial cell ER stress marker CHOP [ Time Frame: Change in baseline endothelial CHOP at 8 weeks ]
    Protein expression of CCAAT-enhancer-binding protein homologous protein (CHOP)

  8. Endothelial cell ER stress marker GRP78 [ Time Frame: Change in baseline endothelial GRP78 at 8 weeks ]
    Protein expression of glucose-regulated protein 78 (GRP78)

  9. Endothelial cell ER stress marker GADD34 [ Time Frame: Change in baseline endothelial GADD34 at 8 weeks ]
    Protein expression of growth arrest and DNA damage-inducible 34 (GADD34)

  10. Endothelial cell oxidative stress marker p47phox [ Time Frame: Change in baseline endothelial p47phox at 8 weeks ]
    Protein expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47phox

  11. Endothelial cell oxidative stress marker NT [ Time Frame: Change in baseline endothelial NT at 8 weeks ]
    Protein expression of nitrotyrosine (NT)

  12. Endothelial cell oxidative stress marker MnSOD [ Time Frame: Change in baseline endothelial MnSOD at 8 weeks ]
    Protein expression of manganese superoxide dismutase (MnSOD)

  13. Endothelial cell oxidative stress marker CuZnSOD [ Time Frame: Change in baseline endothelial CuZnSOD at 8 weeks ]
    Protein expression of copper-zinc SOD (CuZnSOD)

  14. Endothelial cell inflammatory marker p65 [ Time Frame: Change in baseline endothelial p65 at 8 weeks ]
    Protein expression of nuclear factor kappa B phosphorylated p65 subunit

  15. Endothelial cell inflammatory marker IκBα [ Time Frame: Change in baseline endothelial IκBα at 8 weeks ]
    Protein expression of phosphorylated inhibitor of kappa B (IκBα)

  16. Endothelial cell inflammatory marker TNFα [ Time Frame: Change in baseline endothelial TNFα at 8 weeks ]
    Protein expression of tumor necrosis factor-alpha (TNFα)

  17. Endothelial cell inflammatory marker IL-6 [ Time Frame: Change in baseline endothelial IL-6 at 8 weeks ]
    Protein expression of interleukin-6 (IL-6)


Secondary Outcome Measures :
  1. Circulating glucose [ Time Frame: Change in baseline blood glucose at 8 weeks ]
    Blood glucose

  2. Circulating insulin [ Time Frame: Change in baseline insulin at 8 weeks ]
    Blood levels of insulin

  3. Circulating cholesterol [ Time Frame: Change in baseline total cholesterol, LDL cholesterol, and HDL cholesterol at 8 weeks ]
    Blood levels of total cholesterol, LDL cholesterol, and HDL cholesterol

  4. Circulating triglycerides [ Time Frame: Change in baseline triglycerides at 8 weeks ]
    Blood levels of triglycerides

  5. Circulating CRP [ Time Frame: Change in baseline CRP at 8 weeks ]
    Blood levels of C-reactive protein (CRP)

  6. Circulating IL-6 [ Time Frame: Change in baseline IL-6 at 8 weeks ]
    Blood levels of interleukin (IL)-6

  7. Circulating IL-18 [ Time Frame: Change in baseline IL-18 at 8 weeks ]
    Blood levels of interleukin (IL)-18

  8. Circulating IL-10 [ Time Frame: Change in baseline IL-10 at 8 weeks ]
    Blood levels of interleukin (IL)-10

  9. Circulating IL-1β [ Time Frame: Change in baseline IL-1β at 8 weeks ]
    Blood levels of interleukin (IL)-1 beta (β)

  10. Circulating TNFα [ Time Frame: Change in baseline TNFα at 8 weeks ]
    Blood levels of tumor necrosis factor-alpha (TNFα)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04001647


Contacts
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Contact: Nate Bachman, MS 970-491-7281 cvlab@cahs.colostate.edu
Contact: Jennifer Richards, PhD 970-491-6702 cvlab@cahs.colostate.edu

Locations
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United States, Colorado
Colorado State University Recruiting
Fort Collins, Colorado, United States, 80523
Contact: Nate Bachman, MS    970-491-7281    cvlab@cahs.colostate.edu   
Contact: Jennifer Richards, PhD    970-491-6702    cvlab@cahs.colostate.edu   
Principal Investigator: Frank Dinenno, PhD         
Sponsors and Collaborators
Colorado State University
Investigators
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Principal Investigator: Frank Dinenno, PhD Colorado State University

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Responsible Party: Frank Dinenno, Professor, Colorado State University
ClinicalTrials.gov Identifier: NCT04001647     History of Changes
Other Study ID Numbers: TUDCA and Vascular Health
First Posted: June 28, 2019    Key Record Dates
Last Update Posted: June 28, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Frank Dinenno, Colorado State University:
ER stress
Unfolded protein response
Vascular function
Aging
Obesity
TUDCA
Additional relevant MeSH terms:
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Ascorbic Acid
Nitroprusside
Acetylcholine
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Vitamins
Micronutrients
Nutrients
Growth Substances
Vasodilator Agents
Cholinergic Agonists
Cholinergic Agents
Neurotransmitter Agents
Antihypertensive Agents
Nitric Oxide Donors