Targeting ER Stress in Vascular Dysfunction

Early Phase 1TerminatedNCT04001647

Colorado State University17 enrolled

Overview

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.

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

Allocation

Interventions

AcetylcholineDRUG

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 NitroprussideDRUG

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 AcidDRUG

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Endothelium-dependent vasodilation

Blood flow response to increasing doses of acetycholine

Time frame: Change in baseline vasodilation at 8 weeks

Endothelium-independent vasodilation

Blood flow response to increasing doses of sodium nitroprusside

Time frame: Change in baseline vasodilation at 8 weeks

Aortic stiffness

Carotid-femoral pulse-wave velocity

Time frame: Change in baseline pulse-wave velocity at 8 weeks

Endothelial cell ER stress marker ATF6

Protein expression of activating transcription factor 6 (ATF6)

Time frame: 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)

Time frame: 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)

Time frame: Change in baseline endothelial IRE1α at 8 weeks

Endothelial cell ER stress marker CHOP

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

Time frame: Change in baseline endothelial CHOP at 8 weeks

Endothelial cell ER stress marker GRP78

Protein expression of glucose-regulated protein 78 (GRP78)

Time frame: 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)

Time frame: 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

Time frame: Change in baseline endothelial p47phox at 8 weeks

Endothelial cell oxidative stress marker NT

Protein expression of nitrotyrosine (NT)

Time frame: Change in baseline endothelial NT at 8 weeks

Endothelial cell oxidative stress marker MnSOD

Protein expression of manganese superoxide dismutase (MnSOD)

Time frame: Change in baseline endothelial MnSOD at 8 weeks

Endothelial cell oxidative stress marker CuZnSOD

Protein expression of copper-zinc SOD (CuZnSOD)

Time frame: Change in baseline endothelial CuZnSOD at 8 weeks

Endothelial cell inflammatory marker p65

Protein expression of nuclear factor kappa B phosphorylated p65 subunit

Time frame: Change in baseline endothelial p65 at 8 weeks

Endothelial cell inflammatory marker IκBα

Protein expression of phosphorylated inhibitor of kappa B (IκBα)

Time frame: Change in baseline endothelial IκBα at 8 weeks

Endothelial cell inflammatory marker TNFα

Protein expression of tumor necrosis factor-alpha (TNFα)

Time frame: Change in baseline endothelial TNFα at 8 weeks

Endothelial cell inflammatory marker IL-6

Protein expression of interleukin-6 (IL-6)

Time frame: Change in baseline endothelial IL-6 at 8 weeks

Secondary Outcomes

Circulating glucose

Blood glucose

Time frame: Change in baseline blood glucose at 8 weeks

Circulating insulin

Blood levels of insulin

Time frame: Change in baseline insulin at 8 weeks

Circulating cholesterol

Blood levels of total cholesterol, LDL cholesterol, and HDL cholesterol

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

Circulating triglycerides

Blood levels of triglycerides

Time frame: Change in baseline triglycerides at 8 weeks

Circulating CRP

Blood levels of C-reactive protein (CRP)

Time frame: Change in baseline CRP at 8 weeks

Circulating IL-6

Blood levels of interleukin (IL)-6

Time frame: Change in baseline IL-6 at 8 weeks

Circulating IL-18

Blood levels of interleukin (IL)-18

Time frame: Change in baseline IL-18 at 8 weeks

Circulating IL-10

Blood levels of interleukin (IL)-10

Time frame: Change in baseline IL-10 at 8 weeks

Circulating IL-1β

Blood levels of interleukin (IL)-1 beta (β)

Time frame: Change in baseline IL-1β at 8 weeks

Circulating TNFα

Blood levels of tumor necrosis factor-alpha (TNFα)