Cardiovascular disease (CVD) is the leading cause of death in the United States. Aging is the major risk factor for development of CVD. The major age-related arterial phenotypes, which are thought to be responsible for the development of CVD in older adults, are reduced endothelial function and enhanced large artery stiffness. Recently, it has been demonstrated that inhibition of the mTOR signaling pathway, via rapamycin or genetic manipulation, extends lifespan and reduces age-related physiological dysfunction. The proposed studies aim to determine (a) if increased mTOR signaling is responsible for age-related arterial dysfunction and (b) whether dietary rapamycin treatment and activation of AMPK, a putative """"""""rapalog"""""""", can reverse age-related arterial dysfunction. Our laboratory has performed preliminary studies suggesting that arterial activation of mTOR is increased with advancing age and that this is concomitant with age-associated endothelial dysfunction and large artery stiffening known to result from increases in oxidative stress and inflammation. Furthermore, dietary treatment of old mice with mTOR inhibitor, rapamycin, can reverse this age-associated arterial phenotype and improve arterial function. In the present application, by utilizing dietary rapamycin treatment, we will directly assess the role that mTOR plays in modulating transcription factor activity and downstream gene/protein expression and the subsequent effects on arterial phenotype and function. In addition, we will determine if pharmacological activation of AMPK by AICAR will act as a """"""""rapalog,"""""""" mimicking the effects of rapamycin-induced mTOR inhibition on arterial function and phenotype.
Advancing age is associated with arterial dysfunction. The proposed studies aim to determine if elevated arterial mTOR signaling contributes to dysfunction. In addition, we will determine if rapamycin or a rapalog, the AMPK activator AICAR, can reverse age-related arterial dysfunction and the cellular and molecular mechanisms involved.
|Trinity, Joel D; Barrett-O'Keefe, Zachary; Ives, Stephen J et al. (2016) Endogenous endothelin-1 and femoral artery shear rate: impact of age and implications for atherosclerosis. J Hypertens 34:266-73|
|Beyer, Andreas M; Freed, Julie K; Durand, Matthew J et al. (2016) Critical Role for Telomerase in the Mechanism of Flow-Mediated Dilation in the Human Microcirculation. Circ Res 118:856-66|
|Walker, Ashley E; Morgan, R Garrett; Ives, Stephen J et al. (2016) Age-related arterial telomere uncapping and senescence is greater in women compared with men. Exp Gerontol 73:65-71|
|Gibson, Christopher C; Zhu, Weiquan; Davis, Chadwick T et al. (2015) Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulation 131:289-99|
|Walker, Ashley E; Henson, Grant D; Reihl, Kelly D et al. (2015) Greater impairments in cerebral artery compared with skeletal muscle feed artery endothelial function in a mouse model of increased large artery stiffness. J Physiol 593:1931-43|
|Ghosh, Payal; Mora Solis, Fredy R; Dominguez 2nd, James M et al. (2015) Exercise training reverses aging-induced impairment of myogenic constriction in skeletal muscle arterioles. J Appl Physiol (1985) 118:904-11|
|Frech, Tracy; Walker, Ashley E; Barrett-O'Keefe, Zachary et al. (2015) Systemic sclerosis induces pronounced peripheral vascular dysfunction characterized by blunted peripheral vasoreactivity and endothelial dysfunction. Clin Rheumatol 34:905-13|
|Barrett-O'Keefe, Zachary; Ives, Stephen J; Trinity, Joel D et al. (2015) Endothelin-A-mediated vasoconstriction during exercise with advancing age. J Gerontol A Biol Sci Med Sci 70:554-65|
|Donato, Anthony J; Morgan, R Garrett; Walker, Ashley E et al. (2015) Cellular and molecular biology of aging endothelial cells. J Mol Cell Cardiol 89:122-35|
|Venturelli, Massimo; Morgan, Garrett R; Donato, Anthony J et al. (2014) Cellular aging of skeletal muscle: telomeric and free radical evidence that physical inactivity is responsible and not age. Clin Sci (Lond) 127:415-21|
Showing the most recent 10 out of 20 publications