Obligatory role for GPER in cardiovascular aging and disease.
Pharmacological activation of the heptahelical G protein-coupled estrogen receptor (GPER) by selective ligands counteracts multiple aspects of cardiovascular disease. We thus expected that genetic deletion or pharmacological inhibition of GPER would further aggravate such disease states, particularly with age. To the contrary, we found that genetic ablation of Gper in mice prevented cardiovascular pathologies associated with aging by reducing superoxide (⋅O2-) formation by NADPH oxidase (Nox) specifically through reducing the expression of the Nox isoform Nox1 Blocking GPER activity pharmacologically with G36, a synthetic, small-molecule, GPER-selective blocker (GRB), decreased Nox1 abundance and ⋅O2-production to basal amounts in cells exposed to angiotensin II and in mice chronically infused with angiotensin II, reducing arterial hypertension. Thus, this study revealed a role for GPER activity in regulating Nox1 abundance and associated ⋅O2--mediated structural and functional damage that contributes to disease pathology. Our results indicated that GRBs represent a new class of drugs that can reduce Nox abundance and activity and could be used for the treatment of chronic disease processes involving excessive ⋅O2-formation, including arterial hypertension and heart failure.
University of New Mexico Health Sciences Center, Department of Internal Medicine, Albuquerque, NM 87131, USA.
Matthias R
MR
Meyer
University of New Mexico Health Sciences Center, Department of Internal Medicine, Albuquerque, NM 87131, USA.
Natalie C
NC
Fredette
Friedrich-Alexander-University of Erlangen-Nürnberg, Department of Nephropathology, 91054 Erlangen, Germany.
Christoph
C
Daniel
University of New Mexico Health Sciences Center, Department of Internal Medicine, Albuquerque, NM 87131, USA.
Geetanjali
G
Sharma
Friedrich-Alexander-University of Erlangen-Nürnberg, Department of Nephropathology, 91054 Erlangen, Germany.
Kerstin
K
Amann
New Mexico State University, Department of Chemistry and Biochemistry, Las Cruces, NM 88003, USA.
Jeffrey B
JB
Arterburn
University of Zürich, Molecular Internal Medicine, 8057 Zürich, Switzerland.
Matthias
M
Barton
University of New Mexico Health Sciences Center, Department of Internal Medicine, Albuquerque, NM 87131, USA.|University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131, USA.
Eric R
ER
Prossnitz
D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000074624:NADPH Oxidase 1 / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
D052117:Benzodioxoles; C000603178:G36 compound; D011804:Quinolines; D011960:Receptors, Estrogen; D013481:Superoxides; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse