Targeting ER Stress in 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.

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