The Redox-sensitive Induction of the Local Angiotensin System Promotes Both Premature and Replicative Endothelial Senescence: Preventive Effect of a Standardized Crataegus Extract

J Gerontol A Biol Sci Med Sci. 2016 Dec;71(12):1581-1590. doi: 10.1093/gerona/glv213. Epub 2015 Dec 15.


Endothelial senescence, characterized by an irreversible cell cycle arrest, oxidative stress, and downregulation of endothelial nitric oxide synthase (eNOS), has been shown to promote endothelial dysfunction leading to the development of age-related vascular disorders. This study has assessed the possibility that the local angiotensin system promotes endothelial senescence in coronary artery endothelial cells and also the protective effect of the Crataegus extract WS1442, a quantified hawthorn extract. Serial passaging from P1 to P4 (replicative senescence) and treatment of P1 endothelial cells with the eNOS inhibitor L-NAME (premature senescence) promoted acquisition of markers of senescence, enhanced ROS formation, decreased eNOS expression, and upregulation of angiotensin-converting enzyme (ACE) and AT1 receptors. Increased SA-β-gal activity and the upregulation of ACE and AT1R in senescent cells were prevented by antioxidants, an ACE inhibitor, and by an AT1 receptor blocker. WS1442 prevented SA-β-gal activity, the downregulation of eNOS, and oxidative stress in P3 cells. These findings indicate that the impairment of eNOS-derived nitric oxide formation favors a pro-oxidant response triggering the local angiotensin system, which, in turn, promotes endothelial senescence. Such a sequence of events can be effectively inhibited by a standardized polyphenol-rich extract mainly by targeting the oxidative stress.

Keywords: Crataegus extract; Endothelial senescence; Local angiotensin system; Oxidative stress; eNOS; p53/p21 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Angiotensins / physiology*
  • Animals
  • Antioxidants / pharmacology
  • Blotting, Western
  • Cellular Senescence / physiology
  • Coronary Vessels / cytology*
  • Crataegus
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism*
  • Flow Cytometry
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide Synthase Type III / metabolism
  • Oxidation-Reduction
  • Oxidative Stress / physiology*
  • Peptidyl-Dipeptidase A / metabolism
  • Plant Extracts / pharmacology*
  • Reactive Oxygen Species / metabolism
  • Swine


  • Angiotensin-Converting Enzyme Inhibitors
  • Angiotensins
  • Antioxidants
  • Plant Extracts
  • Reactive Oxygen Species
  • crataegus extract
  • Nitric Oxide Synthase Type III
  • ACE protein, human
  • Peptidyl-Dipeptidase A
  • NG-Nitroarginine Methyl Ester