Increased Endothelial Exocytosis and Generation of Endothelin-1 Contributes to Constriction of Aged Arteries

Details

• Personal Author:
  Berkowitz DE ; Flavahan NA ; Flavahan S ; Goel A ; Lowenstein CJ ; Su B
• Description:
  RATIONALE: Circulating levels of endothelin (ET)-1 and endogenous ET(A)-mediated constriction are increased in human aging. The mechanisms responsible are not known. OBJECTIVE: Investigate the storage, release, and activity of ET-1 system in arteries from young and aged Fischer-344 rats. METHODS AND RESULTS: After NO synthase inhibition (L-NAME), thrombin contracted aged arteries, which was inhibited by endothelial denudation, ET(A) receptor antagonism (BQ123), and ECE inhibition (phosphoramidon, SM19712) or by inhibiting exocytosis (TAT-NSF, N-ethylmaleimide-sensitive factor inhibitor). Thrombin did not cause endothelium-dependent contraction of young arteries. In aged but not young arteries, thrombin rapidly increased ET-1 release, which was abolished by endothelium denudation or TAT-NSF. L-NAME did not affect ET-1 release. ET-1 immunofluorescent staining was punctate and distinct from von Willebrand factor (VWF). VWF and ET-1 immunofluorescent intensity was similar in young and aged quiescent arteries. Thrombin rapidly increased ET-1 staining and decreased VWF staining in aged but had no effect in young aortas. After L-NAME, thrombin decreased VWF staining in young aortas. NO donor DEA-NONOate (1 to 100 nmol/L) reversed thrombin-induced exocytosis in young (VWF) but not aged L-NAME-treated aortas (VWF, ET-1). Expression of preproET-1 mRNA and ECE-1 mRNA were increased in aged compared to young endothelium. BigET-1 levels and contraction to exogenous BigET-1 (but not ET-1) were also increased in aged compared to young arteries. CONCLUSIONS: The stimulated exocytotic release of ET-1 is dramatically increased in aged endothelium. This reflects increased reactivity of exocytosis, increased expression and storage of ET-1 precursor peptides, and increased expression of ECE-1. Altered endothelial exocytosis of ET-1 and other mediators may contribute to cardiovascular pathology in aging [Description provided by NIOSH]
• Subjects:
  Age Factors Animals Cardiovascular System Energy Metabolism Laboratories Occupational Health Pathology Safety
• Keywords:
  Age-factors Animal-studies Author Keywords: Aorta Cardiovascular-system Cell-biology Cellular-reactions Circulatory-system Dose-response Enzyme-inhibitors Laboratory-animals Mesenteric Arteries Metabolism Peptides Pharmacology Recombinant-DNA Thrombin Von Willebrand Factor Weibel-Palade Bodies

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• ISSN:
  0009-7330
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Maryland ; OSHA Region 3
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  242-251
• Volume:
  107
• Issue:
  2
• NIOSHTIC Number:
  nn:20037500
• Citation:
  Circ Res 2010 Jul; 107(2):242-251
• Contact Point Address:
  Nick Flavahan, Department of Anesthesiology, Johns Hopkins University, Ross-R1159, 720 Rutland Ave, Baltimore, MD 21205
• Email:
  nflavah1@jhmi.edu
• CAS Registry Number:
  Hydrazine (CAS RN 302-01-2) ; Nitric oxide (CAS RN 10102-43-9)
• Federal Fiscal Year:
  2010
• Performing Organization:
  Johns Hopkins University
• Peer Reviewed:
  True
• Start Date:
  20050801
• Source Full Name:
  Circulation Research
• End Date:
  20100731
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:6acf0d2db5d930583d09c2b4107d59e067a25c1fb35ab0255bfde60054f017742608b83ab616ff05de557fe7faac835c29e5854139dea011eb912b4910bb64f8
• Download URL:
  https://stacks.cdc.gov/view/cdc/188589/cdc_188589_DS1.pdf
• File Type:
  [PDF - 5.54 MB ]