Clinical trial NCT04001647: Targeting ER Stress in Vascular Dysfunction
Official title: Targeting Endoplasmic Reticulum Stress in Aging- and Obesity-Induced Vascular Dysfunction
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: EARLY_PHASE1
Conditions: Vasodilation
Arterial Stiffness
Keywords: ER stress
Unfolded protein response
Vascular function
Aging
Obesity
TUDCA
Lead sponsor: Colorado State University
Sponsor class: OTHER
First posted: 2019-06-28
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: BASIC_SCIENCE

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.

Eligibility 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

Primary outcomes:
measure: Endothelium-dependent vasodilation
timeFrame: Change in baseline vasodilation at 8 weeks
measure: Endothelium-independent vasodilation
timeFrame: Change in baseline vasodilation at 8 weeks
measure: Aortic stiffness
timeFrame: Change in baseline pulse-wave velocity at 8 weeks
measure: Endothelial cell ER stress marker ATF6
timeFrame: Change in baseline endothelial ATF6 at 8 weeks
measure: Endothelial cell ER stress marker PERK
timeFrame: Change in baseline endothelial PERK at 8 weeks
measure: Endothelial cell ER stress marker IRE1α
timeFrame: Change in baseline endothelial IRE1α at 8 weeks
measure: Endothelial cell ER stress marker CHOP
timeFrame: Change in baseline endothelial CHOP at 8 weeks
measure: Endothelial cell ER stress marker GRP78
timeFrame: Change in baseline endothelial GRP78 at 8 weeks
measure: Endothelial cell ER stress marker GADD34
timeFrame: Change in baseline endothelial GADD34 at 8 weeks
measure: Endothelial cell oxidative stress marker p47phox
timeFrame: Change in baseline endothelial p47phox at 8 weeks
measure: Endothelial cell oxidative stress marker NT
timeFrame: Change in baseline endothelial NT at 8 weeks
measure: Endothelial cell oxidative stress marker MnSOD
timeFrame: Change in baseline endothelial MnSOD at 8 weeks
measure: Endothelial cell oxidative stress marker CuZnSOD
timeFrame: Change in baseline endothelial CuZnSOD at 8 weeks
measure: Endothelial cell inflammatory marker p65
timeFrame: Change in baseline endothelial p65 at 8 weeks
measure: Endothelial cell inflammatory marker IκBα
timeFrame: Change in baseline endothelial IκBα at 8 weeks
measure: Endothelial cell inflammatory marker TNFα
timeFrame: Change in baseline endothelial TNFα at 8 weeks
measure: Endothelial cell inflammatory marker IL-6
timeFrame: Change in baseline endothelial IL-6 at 8 weeks
Secondary outcomes:
measure: Circulating glucose
timeFrame: Change in baseline blood glucose at 8 weeks
measure: Circulating insulin
timeFrame: Change in baseline insulin at 8 weeks
measure: Circulating cholesterol
timeFrame: Change in baseline total cholesterol, LDL cholesterol, and HDL cholesterol at 8 weeks
measure: Circulating triglycerides
timeFrame: Change in baseline triglycerides at 8 weeks
measure: Circulating CRP
timeFrame: Change in baseline CRP at 8 weeks
measure: Circulating IL-6
timeFrame: Change in baseline IL-6 at 8 weeks
measure: Circulating IL-18
timeFrame: Change in baseline IL-18 at 8 weeks
measure: Circulating IL-10
timeFrame: Change in baseline IL-10 at 8 weeks
measure: Circulating IL-1β
timeFrame: Change in baseline IL-1β at 8 weeks
measure: Circulating TNFα
timeFrame: Change in baseline TNFα at 8 weeks
Other outcomes:
Locations:
city: Fort Collins
country: United States
facility: Colorado State University
state: Colorado
Study officials:
affiliation: Colorado State University
name: Frank Dinenno, PhD
role: PRINCIPAL_INVESTIGATOR
References: