title: GPER is required for the age-dependent upregulation of the myocardial endothelin system.
abstract: OBJECTIVE
  Cardiac aging is associated with progressive structural changes and functional impairment, such as left ventricular hypertrophy, fibrosis and diastolic dysfunction. Aging also increases myocardial activity of endothelin-1 (ET-1), a multifunctional peptide with growth-promoting and pro-fibrotic activity. Because the G protein-coupled estrogen receptor (GPER) regulates vascular responsiveness to ET-1, we investigated whether GPER also plays a role in the regulation of the myocardial endothelin system with aging.
  
  
  METHODS
  Young (4month-old) and aged (24month-old) wild-type and Gper-deficient (Gper(-/-)) mice were studied. Gene expression levels of prepro-ET-1, endothelin converting enzymes ECE-1 and ECE-2, and endothelin ETA and ETB receptors were determined by qPCR in left ventricular myocardium.
  
  
  RESULTS
  Aging markedly increased steady-state mRNA expression levels of ECE-1, ECE-2, ETA and ETB receptors (each p<0.001 vs. young mice). Deletion of Gper inhibited the age-dependent increase in ECE-2 and ETB receptor mRNA levels (57% and 40% reduction, respectively, each p<0.01 vs. wild-type mice), whereas gene expression of prepro-ET-1, ECE-1, and the ETA receptor was unaffected in Gper(-/-) mice.
  
  
  CONCLUSIONS
  We identified a novel regulatory mechanism through which the endogenous Gper facilitates the age-dependent increase in myocardial expression of ECE-2 and the ETB receptor, which is compatible with an activating role of GPER for the local endothelin system with aging. Targeting GPER signaling by selective antagonists may therefore be considered a new therapeutic approach to reduce age-dependent increased ET-1 activity and the associated development of left ventricular hypertrophy, fibrosis and heart failure.
authors.affiliation: Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States. Electronic address: matthias.meyer@ksa.ch.
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Meyer
authors.affiliation: Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Fredette
authors.affiliation: Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Sharma
authors.affiliation: Molecular Internal Medicine, University of Zürich, Zürich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Barton
authors.affiliation: Department of Internal Medicine, 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 / Q000378:metabolism*; D000818:Animals; D016232:Endothelins / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D016232:Endothelins; C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled
keywords: Aging; ET-1; Endothelin converting enzyme; Endothelin receptor; Estrogen receptor; GPR30; Heart; Myocardium