Targeting ER Stress in Vascular Dysfunction

Arterial Stiffness Clinical Trial

Official title:

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

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT04001647
• Other study ID #: TUDCA and Vascular Health
• Status: Suspended
• Phase: Early Phase 1
• Start date: June 1, 2019
• Est. completion date: August 30, 2023

Study information

• Verified date: December 2022
• Source: Colorado State University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 60
• Est. completion date: August 30, 2023
• Est. primary completion date: June 1, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Arterial Stiffness
• Vasodilation

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
United States	Colorado State University	Fort Collins	Colorado

Sponsors (1)

Lead Sponsor	Collaborator
Colorado State University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Endothelium-dependent vasodilation	Blood flow response to increasing doses of acetycholine	Change in baseline vasodilation at 8 weeks
Primary	Endothelium-independent vasodilation	Blood flow response to increasing doses of sodium nitroprusside	Change in baseline vasodilation at 8 weeks
Primary	Aortic stiffness	Carotid-femoral pulse-wave velocity	Change in baseline pulse-wave velocity at 8 weeks
Primary	Endothelial cell ER stress marker ATF6	Protein expression of activating transcription factor 6 (ATF6)	Change in baseline endothelial ATF6 at 8 weeks
Primary	Endothelial cell ER stress marker PERK	Protein expression of RNA-dependent protein kinase- like ER eukaryotic initiation factor-2a kinase (PERK)	Change in baseline endothelial PERK at 8 weeks
Primary	Endothelial cell ER stress marker IRE1a	Protein expression of inositol-requiring ER-to-nucleus signaling protein 1(IRE1a)	Change in baseline endothelial IRE1a at 8 weeks
Primary	Endothelial cell ER stress marker CHOP	Protein expression of CCAAT-enhancer-binding protein homologous protein (CHOP)	Change in baseline endothelial CHOP at 8 weeks
Primary	Endothelial cell ER stress marker GRP78	Protein expression of glucose-regulated protein 78 (GRP78)	Change in baseline endothelial GRP78 at 8 weeks
Primary	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
Primary	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
Primary	Endothelial cell oxidative stress marker NT	Protein expression of nitrotyrosine (NT)	Change in baseline endothelial NT at 8 weeks
Primary	Endothelial cell oxidative stress marker MnSOD	Protein expression of manganese superoxide dismutase (MnSOD)	Change in baseline endothelial MnSOD at 8 weeks
Primary	Endothelial cell oxidative stress marker CuZnSOD	Protein expression of copper-zinc SOD (CuZnSOD)	Change in baseline endothelial CuZnSOD at 8 weeks
Primary	Endothelial cell inflammatory marker p65	Protein expression of nuclear factor kappa B phosphorylated p65 subunit	Change in baseline endothelial p65 at 8 weeks
Primary	Endothelial cell inflammatory marker I?Ba	Protein expression of phosphorylated inhibitor of kappa B (I?Ba)	Change in baseline endothelial I?Ba at 8 weeks
Primary	Endothelial cell inflammatory marker TNFa	Protein expression of tumor necrosis factor-alpha (TNFa)	Change in baseline endothelial TNFa at 8 weeks
Primary	Endothelial cell inflammatory marker IL-6	Protein expression of interleukin-6 (IL-6)	Change in baseline endothelial IL-6 at 8 weeks
Secondary	Circulating glucose	Blood glucose	Change in baseline blood glucose at 8 weeks
Secondary	Circulating insulin	Blood levels of insulin	Change in baseline insulin at 8 weeks
Secondary	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
Secondary	Circulating triglycerides	Blood levels of triglycerides	Change in baseline triglycerides at 8 weeks
Secondary	Circulating CRP	Blood levels of C-reactive protein (CRP)	Change in baseline CRP at 8 weeks
Secondary	Circulating IL-6	Blood levels of interleukin (IL)-6	Change in baseline IL-6 at 8 weeks
Secondary	Circulating IL-18	Blood levels of interleukin (IL)-18	Change in baseline IL-18 at 8 weeks
Secondary	Circulating IL-10	Blood levels of interleukin (IL)-10	Change in baseline IL-10 at 8 weeks
Secondary	Circulating IL-1ß	Blood levels of interleukin (IL)-1 beta (ß)	Change in baseline IL-1ß at 8 weeks
Secondary	Circulating TNFa	Blood levels of tumor necrosis factor-alpha (TNFa)	Change in baseline TNFa at 8 weeks