Activation of GPER ameliorates experimental pulmonary hypertension in male rats.
BACKGROUND
Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling that leads to pulmonary congestion, uncompensated right-ventricle (RV) failure, and premature death. Preclinical studies have demonstrated that the G protein-coupled estrogen receptor (GPER) is cardioprotective in male rats and that its activation elicits vascular relaxation in rats of either sex.


OBJECTIVE
To study the effects of GPER on the cardiopulmonary system by the administration of its selective agonist G1 in male rats with monocrotaline (MCT)-induced PH.


METHODS
Rats received a single intraperitoneal injection of MCT (60mg/kg) for PH induction. Experimental groups were as follows: control, MCT+vehicle, and MCT+G1 (400μg/kg/daysubcutaneous). Animals (n=5pergroup) were treated with vehicle or G1 for 14days after disease onset.


RESULTS
Activation of GPER attenuated exercise intolerance and reduced RV overload in PH rats. Rats with PH exhibited echocardiographic alterations, such as reduced pulmonary flow, RV hypertrophy, and left-ventricle dysfunction, by the end of protocol. G1 treatment reversed these PH-related abnormalities of cardiopulmonary function and structure, in part by promoting pulmonary endothelial nitric oxide synthesis, Ca2+handling regulation and reduction of inflammation in cardiomyocytes, and a decrease of collagen deposition by acting in pulmonary and cardiac fibroblasts.


CONCLUSIONS
G1 was effective to reverse PH-induced RV dysfunction and exercise intolerance in male rats, a finding that have important implications for ongoing clinical evaluation of new cardioprotective and vasodilator drugs for the treatment of the disease.
Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Allan K
AK
Alencar
Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Guilherme C
GC
Montes
Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Tadeu
T
Montagnoli
Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Ananssa M
AM
Silva
Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Sabrina T
ST
Martinez
Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Aline G
AG
Fraga
Department of Anesthesiology, Wake Forest University, Winston-Salem, NC, USA.
Hao
H
Wang
Department of Anesthesiology, Wake Forest University, Winston-Salem, NC, USA.
Leanne
L
Groban
Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Roberto T
RT
Sudo
Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. Electronic address: gsudo@icb.ufrj.br.
Gisele
G
Zapata-Sudo
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D006976:Hypertension, Pulmonary / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism*
D000959:Antihypertensive Agents; C520305:Gper1 protein, rat; D043562:Receptors, G-Protein-Coupled
GPER; Monocrotaline; Right ventricular dysfunction; Vascular remodeling