Targeting ER Stress in Vascular Dysfunction

Targeting Endoplasmic Reticulum Stress in Aging- and Obesity-Induced Vascular Dysfunction

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.

Study Overview

• Status: Terminated
• Conditions: Vasodilation; Arterial Stiffness
• Intervention / Treatment: Drug: Acetylcholine; Drug: Sodium Nitroprusside; Drug: Ascorbic Acid

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.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Fort Collins, Colorado, United States, 80523
      • Colorado State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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: Vitamin C; AA
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 Names: 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 Names: 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: Vitamin C; AA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Circulating glucose	Blood glucose	Change in baseline blood glucose at 8 weeks
Circulating insulin	Blood levels of insulin	Change in baseline insulin at 8 weeks
Circulating cholesterol	Blood levels of total cholesterol, LDL cholesterol, and HDL cholesterol	Change in baseline total cholesterol, LDL cholesterol, and HDL cholesterol at 8 weeks
Circulating triglycerides	Blood levels of triglycerides	Change in baseline triglycerides at 8 weeks
Circulating CRP	Blood levels of C-reactive protein (CRP)	Change in baseline CRP at 8 weeks
Circulating IL-6	Blood levels of interleukin (IL)-6	Change in baseline IL-6 at 8 weeks
Circulating IL-18	Blood levels of interleukin (IL)-18	Change in baseline IL-18 at 8 weeks
Circulating IL-10	Blood levels of interleukin (IL)-10	Change in baseline IL-10 at 8 weeks
Circulating IL-1β	Blood levels of interleukin (IL)-1 beta (β)	Change in baseline IL-1β at 8 weeks
Circulating TNFα	Blood levels of tumor necrosis factor-alpha (TNFα)	Change in baseline TNFα at 8 weeks

Collaborators and Investigators

• Sponsor: Colorado State University
• Investigators: Principal Investigator: Frank Dinenno, PhD, Colorado State University

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2019
• Primary Completion (Actual): August 16, 2022
• Study Completion (Actual): August 16, 2022

Study Registration Dates

• First Submitted: June 21, 2019
• First Submitted That Met QC Criteria: June 26, 2019
• First Posted (Actual): June 28, 2019

Study Record Updates

• Last Update Posted (Actual): April 8, 2025
• Last Update Submitted That Met QC Criteria: April 7, 2025
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Obesity; Aging; Vascular function; TUDCA; ER stress; Unfolded protein response
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Micronutrients; Antioxidants; Protective Agents; Vitamins; Vasodilator Agents; Antihypertensive Agents; Cholinergic Agents; Cholinergic Agonists; Nitric Oxide Donors; Ascorbic Acid; Acetylcholine; Nitroprusside
• Other Study ID Numbers: TUDCA and Vascular Health

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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