Decreased autophagy leads to proteotoxicity and senescence in hypertension-associated premature vascular aging

Project: Research


  • Cam McCarthy (PI)


Hypertension has been described as a condition of premature vascular aging (relative to actual chronological age). In fact, many factors that contribute to the deterioration of vascular function as we age are accelerated in hypertension. Nonetheless, the precise mechanisms that underlie the aged phenotype in arteries from hypertensive animals remain elusive.Cellular senescence is an age-related physiologic process in which cells undergo irreversible growth arrest. This replicative exhaustion is attributed to the limits imposed by critically short telomeres, which provoke a persistent DNA damage response and genomic instability. While controlled senescence negatively regulates cell proliferation and promotes tissue regeneration, uncontrolled senescence can contribute to disease pathogenesis by presenting the senescence-associated secretory phenotype (SASP), in which molecules such as cytokines, matrix metalloproteases, and reactive oxygen species are released into tissue microenvironments. The aged phenotype is classically viewed as the accumulation of damaged cellular macromolecules and organelles, including the accumulation of misfolded protein aggregates. In fact, the accumulation of misfolded-aggregated proteins is linked to an increasing number of degenerative diseases, including hypertension. Although protein damage and misfolding are an inevitable consequence of normal cellular function, multiple proteostasis systems are devoted to the repair or clearance of damaged proteins and prevent aggregation. Autophagy is the constitutive and basally active recycling mechanism responsible for protein quality control. Our preliminary data has revealed that autophagic activity is diminished, while amyloid oligomers and senescent cells are increased in resistance arteries of hypertensive rats. Nonetheless, the connection between autophagy to proteotoxicity and senescence in hypertension is currently unknown. Therefore, we propose the novel hypothesis that decreased autophagy in arteries [endothelial cells and vascular smooth muscle cells (VSMCs)] leads to the buildup of protein aggregates triggering senescence and premature vascular aging in hypertension.
Award amount$106,532.00
Award date07/01/2018
Program typePostdoctoral Fellowship
Award ID18POST34060003
Effective start/end date07/01/201806/30/2020