Targeting Endoplasmic Reticulum Stress in Aging- and Obesity-Induced Vascular Dysfunction
Description: Endoplasmic reticulum (ER) stress has emerged as an important mediator of disease pathology, and recent studies performed in cell culture and experimental animal models have demonstrated that inhibition of ER stress prevents or reverses numerous chronic diseases. 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, and both predict cardiovascular events in older individuals. Aging often coincides with obesity, another independent risk factor for CVD. It is currently unclear how these two physiological states interact to modulate vascular function, and whether the combination of aging and obesity has compounding effects on endothelial dysfunction and arterial stiffness. Further, it is unknown whether vascular dysfunction is driven by the same underlying cellular mechanisms in aging and obesity. Our preliminary results suggest that ER stress may be an important factor in aging- and obesity-related vascular dysfunction, and we have data demonstrating that middle-aged and older obese adults with endothelial dysfunction display evidence of ER stress within biopsied endothelial cells. Thus, 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 tauro-ursodeoxycholic acid (TUDCA), an inhibitor of ER stress, to reduce endothelial cell ER stress and improve vascular function in these at-risk individuals. We will determine the relative contributions of aging and obesity on vascular dysfunction and endothelial ER stress in humans (Aim 1), and whether 8 weeks of TUDCA administration improves vascular function and ER stress in older lean and obese humans (Aim 2). Our primary hypothesis is that TUDCA will reduce endothelial cell ER stress and improve endothelial function and arterial stiffness in older and/or obese individuals, and this effect will be most pronounced in older obese humans. Our secondary hypothesis is that inhibition of ER stress via TUDCA will improve vascular function via a reduction in oxidative stress. 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.
Funder: American Heart Association
Amount: $300,000
Funding type: research
Funder scheme: Transformational Project Award
Start date: 2018-07-01
End date: 2018-11-07
Investigators: Frank DINENNO, Frank DINENNO
Institution: Colorado State University
Funded outputs count: 0
Funder award ID: 18TPA34170461
OpenAlex ID: G2237558787