title: Endothelin-1 but not angiotensin II contributes to functional aging in murine carotid arteries.
abstract: OBJECTIVE
  Aging is a major risk factor for carotid artery disease and stroke. Endothelin-1 (ET-1) and angiotensin II (Ang II) are important modifiers of vascular disease, partly through increased activity of NADPH oxidase and vasoconstrictor prostanoids. Since the renin-angiotensin and endothelin systems become activated with age, we hypothesized that aging affects NADPH oxidase- and prostanoid-dependent contractions to ET-1 and Ang II.
  
  
  METHODS
  Carotid artery rings of young (4 month-old) and old (24 month-old) C57BL6 mice were pretreated with the NO synthase inhibitor L-NAME to exclude differential effects of NO. Contractions to ET-1 and Ang II were determined in the presence and absence of the NADPH oxidase-selective inhibitor gp91ds-tat or the thromboxane-prostanoid receptor antagonist SQ 29,548. Gene expression of endothelin and angiotensin receptors was measured by qPCR.
  
  
  RESULTS
  Aging reduced ET-1-induced contractions and diminished ETA but increased ETB receptor gene expression levels. Gp91ds-tat inhibited contractions to ET-1 in young and to a greater extent in old animals, whereas SQ 29,548 had no effect. Ang II-induced contractions were weak compared to ET-1 and unaffected by aging, gp91ds-tat, and SQ 29,548. Aging had also no effect on AT1A and AT1B receptor gene expression levels.
  
  
  CONCLUSIONS
  Aging in carotid arteries decreases ETA receptor gene expression and responsiveness to ET-1, which nevertheless becomes increasingly dependent upon NAPDH oxidase activity with age; responses to Ang II and gene expression of its receptors are however unaffected. These findings suggest that physiological aging differentially regulates functional responses to G protein-coupled receptor agonists and the signaling pathways associated with their activation.
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Meyer
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Fredette
authors.affiliation: Molecular Internal Medicine, University of Zürich, Zürich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Barton
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States. Electronic address: eprossnitz@salud.unm.edu.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Prossnitz
mesh_terms: D000375:Aging / Q000187:drug effects / Q000502:physiology*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D017536:Carotid Artery, Common / Q000187:drug effects / Q000502:physiology*; D019332:Endothelin-1 / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D017466:Receptors, Endothelin; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D019255:NADPH Oxidases
keywords: Age; Angiotensin II (PubChem CID: 172198); Artery; Atherosclerosis; Cyclooxygenase; Dementia; Endothelin-1 (PubChem CID: 16212950); GPCR; L-N(G)-nitroarginine methyl ester (PubChem CID: 39836); NADPH; Nox; Oxidative stress; Prostanoid; ROS; Reactive oxygen species; SQ 29,548 (PubChem CID: 5271); Stroke; Superoxide; Vascular; gp91ds-tat