Mechanisms of impaired red blood cell ATP release in older adults: implications for altered vascular control with age
Date
2018
Authors
Racine, Matthew L., author
Dinenno, Frank A., advisor
Amberg, Gregory, committee member
Chicco, Adam, committee member
Gentile, Christopher, committee member
Journal Title
Journal ISSN
Volume Title
Abstract
The following dissertation is comprised of a series of experiments with the overall aim of determining the mechanisms of impaired ATP release from red blood cells (RBCs) of healthy older adults in response to hemoglobin deoxygenation and identifying a potential role of this impairment in the declines in vascular control of peripheral blood flow with advancing age. Advancing age is the primary risk factor for cardiovascular disease (CVD), which is the leading cause of death in societies today and is strongly associated with arterial dysfunction. Furthermore, impairments in vascular control and the subsequent regulation of tissue blood flow and oxygen delivery contribute to vascular pathologies such as atherosclerosis and ischemic disease, as well as the age-associated declines in functional capacity, exercise tolerance, and overall quality of life. Thus, understanding the mechanisms of the age-related impairments in vascular control and identifying potential therapeutic targets holds significant potential for reducing the healthcare burden associated with a rapidly aging population. Accordingly, the ultimate goal of this dissertation is to determine if an in vivo pharmacological approach can be utilized to treat the age-related declines in RBC ATP release, thereby restoring circulating ATP responses and subsequent vascular control during the physiological stimuli of hypoxia and exercise in healthy older adults. The key novel findings of this dissertation are that (i) age-associated declines in RBC deformability are the primary mechanism of impaired deoxygenation-induced ATP release from RBCs of healthy older adults; (ii) primary (healthy) aging is not associated with a global decline in RBC function given that inhibition of cyclic AMP hydrolysis by phosphodiesterase 3 did not improve deoxygenation-induced ATP release from RBCs of older adults and that the cellular responses to Gi protein activation remained intact with age; and (iii) that systemic Rho-kinase inhibition via administration of fasudil improves the age-related impairments in vascular control and circulating ATP during systemic hypoxia and exercise, which may be related to enhanced RBC ATP release and NO bioavailability. These findings are the first to identify a role for Rho-kinase inhibition in improving these physiological responses in healthy older adults and are therefore clinically significant for aging population in which impaired vascular control contributes to elevations in cardiovascular disease risk and declines in exercise tolerance, functional independence and overall quality of life.