Endothelial and systemic upregulation of miR-34a-5p fine-tunes senescence in progeria

Aging (Albany NY). 2022 Jan 12;14(1):195-224. doi: 10.18632/aging.203820. Epub 2022 Jan 12.


Endothelial defects significantly contribute to cardiovascular pathology in the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). Using an endothelium-specific progeria mouse model, we identify a novel, endothelium-specific microRNA (miR) signature linked to the p53-senescence pathway and a senescence-associated secretory phenotype (SASP). Progerin-expressing endothelial cells exert profound cell-non-autonomous effects initiating senescence in non-endothelial cell populations and causing immune cell infiltrates around blood vessels. Comparative miR expression analyses revealed unique upregulation of senescence-associated miR34a-5p in endothelial cells with strong accumulation at atheroprone aortic arch regions but also, in whole cardiac- and lung tissues as well as in the circulation of progeria mice. Mechanistically, miR34a-5p knockdown reduced not only p53 levels but also late-stage senescence regulator p16 with no effect on p21 levels, while p53 knockdown reduced miR34a-5p and partially rescued p21-mediated cell cycle inhibition with a moderate effect on SASP. These data demonstrate that miR34a-5p reinforces two separate senescence regulating branches in progerin-expressing endothelial cells, the p53- and p16-associated pathways, which synergistically maintain a senescence phenotype that contributes to cardiovascular pathology. Thus, the key function of circulatory miR34a-5p in endothelial dysfunction-linked cardiovascular pathology offers novel routes for diagnosis, prognosis and treatment for cardiovascular aging in HGPS and potentially geriatric patients.

Keywords: Hutchinson-Gilford progeria syndrome; cardiovascular disease; endothelial senescence; senescence-associated micro RNAs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Aorta, Thoracic / metabolism
  • Aorta, Thoracic / pathology
  • Atherosclerosis / metabolism
  • Cellular Senescence
  • Down-Regulation
  • Endothelium, Vascular / metabolism*
  • Gene Expression Regulation / physiology*
  • Lamin Type A / genetics
  • Lamin Type A / metabolism*
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Paracrine Communication / physiology
  • Progeria / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation / physiology*


  • Lamin Type A
  • MIRN34a microRNA, mouse
  • MicroRNAs
  • RNA, Messenger
  • Tumor Suppressor Protein p53
  • prelamin A