Targeting ER Stress in Vascular Dysfunction

NCT04001647 | Terminated Early Phase 1 FDA Drug

• 1 other identifier: TUDCA and Vascular Health
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

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.

Conditions

Vasodilation; Arterial Stiffness

Keywords

ER stress; Unfolded protein response; Vascular function; Aging; Obesity; TUDCA

Outcome Measures

Primary Outcomes (17)

• Endothelium-dependent vasodilation

  Blood flow response to increasing doses of acetycholine

  Change in baseline vasodilation at 8 weeks

• Endothelium-independent vasodilation

  Blood flow response to increasing doses of sodium nitroprusside

  Change in baseline vasodilation at 8 weeks

• Aortic stiffness

  Carotid-femoral pulse-wave velocity

  Change in baseline pulse-wave velocity at 8 weeks

• Endothelial cell ER stress marker ATF6

  Protein expression of activating transcription factor 6 (ATF6)

  Change in baseline endothelial ATF6 at 8 weeks

• Endothelial cell ER stress marker PERK

  Protein expression of RNA-dependent protein kinase- like ER eukaryotic initiation factor-2α kinase (PERK)

  Change in baseline endothelial PERK at 8 weeks

• Endothelial cell ER stress marker IRE1α

  Protein expression of inositol-requiring ER-to-nucleus signaling protein 1(IRE1α)

  Change in baseline endothelial IRE1α at 8 weeks

• Endothelial cell ER stress marker CHOP

  Protein expression of CCAAT-enhancer-binding protein homologous protein (CHOP)

  Change in baseline endothelial CHOP at 8 weeks

• Endothelial cell ER stress marker GRP78

  Protein expression of glucose-regulated protein 78 (GRP78)

  Change in baseline endothelial GRP78 at 8 weeks

• Endothelial cell ER stress marker GADD34

  Protein expression of growth arrest and DNA damage-inducible 34 (GADD34)

  Change in baseline endothelial GADD34 at 8 weeks

• Endothelial cell oxidative stress marker p47phox

  Protein expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47phox

  Change in baseline endothelial p47phox at 8 weeks

• Endothelial cell oxidative stress marker NT

  Protein expression of nitrotyrosine (NT)

  Change in baseline endothelial NT at 8 weeks

• Endothelial cell oxidative stress marker MnSOD

  Protein expression of manganese superoxide dismutase (MnSOD)

  Change in baseline endothelial MnSOD at 8 weeks

• Endothelial cell oxidative stress marker CuZnSOD

  Protein expression of copper-zinc SOD (CuZnSOD)

  Change in baseline endothelial CuZnSOD at 8 weeks

• Endothelial cell inflammatory marker p65

  Protein expression of nuclear factor kappa B phosphorylated p65 subunit

  Change in baseline endothelial p65 at 8 weeks

• Endothelial cell inflammatory marker IκBα

  Protein expression of phosphorylated inhibitor of kappa B (IκBα)

  Change in baseline endothelial IκBα at 8 weeks

• Endothelial cell inflammatory marker TNFα

  Protein expression of tumor necrosis factor-alpha (TNFα)

  Change in baseline endothelial TNFα at 8 weeks

• Endothelial cell inflammatory marker IL-6

  Protein expression of interleukin-6 (IL-6)

  Change in baseline endothelial IL-6 at 8 weeks

Secondary Outcomes (10)

• Circulating glucose

  Change in baseline blood glucose at 8 weeks

• Circulating insulin

  Change in baseline insulin at 8 weeks

• Circulating cholesterol

  Change in baseline total cholesterol, LDL cholesterol, and HDL cholesterol at 8 weeks

• Circulating triglycerides

  Change in baseline triglycerides at 8 weeks

• Circulating CRP

  Change in baseline CRP at 8 weeks

Study Arms (2)

TUDCA

EXPERIMENTAL

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; Drug: Sodium Nitroprusside; Drug: Ascorbic Acid

Placebo

PLACEBO COMPARATOR

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; Drug: Sodium Nitroprusside; Drug: Ascorbic Acid

Interventions

Acetylcholine DRUG

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.

Also known as: ACh

Placebo; TUDCA

Sodium Nitroprusside DRUG

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.

Also known as: SNP

Placebo; TUDCA

Ascorbic Acid DRUG

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.

Also known as: AA, Vitamin C

Placebo; TUDCA

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Colorado State University: lead

Study Sites (1)

Colorado State University

Fort Collins, Colorado, 80523, United States

Location

MeSH Terms

Conditions

Aneurysm; Obesity

Interventions

Acetylcholine; Nitroprusside; Ascorbic Acid

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Biogenic Amines; Amines; Organic Chemicals; Ferricyanides; Cyanides; Anions; Ions; Electrolytes; Inorganic Chemicals; Ferric Compounds; Iron Compounds; Hydrogen Cyanide; Nitrogen Compounds; Sugar Acids; Acids, Acyclic; Carboxylic Acids; Hydroxy Acids; Carbohydrates

Study Officials

• Frank Dinenno, PhD

  Colorado State University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: 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.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: June 21, 2019
• First Posted: June 28, 2019
• Study Start: June 1, 2019
• Primary Completion: August 16, 2022
• Study Completion: August 16, 2022
• Last Updated: April 8, 2025

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)