Dataset Information

Activation of GPER ameliorates experimental pulmonary hypertension in male rats.

ABSTRACT:

Rationale

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.

Objectives

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.

Measurements and main 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.

SUBMITTER: Alencar AK

PROVIDER: S-EPMC5183553 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

Activation of GPER ameliorates experimental pulmonary hypertension in male rats.

Alencar Allan K AK Montes Guilherme C GC Montagnoli Tadeu T Silva Ananssa M AM Martinez Sabrina T ST Fraga Aline G AG Wang Hao H Groban Leanne L Sudo Roberto T RT Zapata-Sudo Gisele G

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 20161109

<h4>Rationale</h4>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.<h4>Objectives</h4>To study the effects of GPER on the cardiopulmonary system by the administration of its ...[more]

PMID: 27836751

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Project description:Background: The beneficial effects of parasympathetic stimulation in pulmonary arterial hypertension (PAH) have been reported. However, the specific mechanism has not been completely clarified. Donepezil, an oral cholinesterase inhibitor, enhances parasympathetic activity by inhibiting acetylcholinesterase, whose therapeutic effects in PAH and its mechanism deserve to be investigated. Methods: The PAH model was established by a single intraperitoneal injection of monocrotaline (MCT, 50 mg/kg) in adult male Sprague-Dawley rats. Donepezil was administered via intraperitoneal injection daily after 1 week of MCT administration. At the end of the study, PAH status was confirmed by echocardiography and hemodynamic measurement. Testing for acetylcholinesterase activity and cholinergic receptor expression was used to evaluate parasympathetic activity. Indicators of pulmonary arterial remodeling and right ventricular (RV) dysfunction were assayed. The proliferative and apoptotic ability of pulmonary arterial smooth muscle cells (PASMCs), inflammatory reaction, macrophage infiltration in the lung, and activation of bone marrow-derived macrophages (BMDMs) were also tested. PASMCs from the MCT-treated rats were co-cultured with the supernatant of BMDMs treated with donepezil, and then, the proliferation and apoptosis of PASMCs were evaluated. Results: Donepezil treatment effectively enhanced parasympathetic activity. Furthermore, it markedly reduced mean pulmonary arterial pressure and RV systolic pressure in the MCT-treated rats, as well as reversed pulmonary arterial remodeling and RV dysfunction. Donepezil also reduced the proliferation and promoted the apoptosis of PASMCs in the MCT-treated rats. In addition, it suppressed the inflammatory response and macrophage activation in both lung tissue and BMDMs in the model rats. More importantly, donepezil reduced the proliferation and promoted the apoptosis of PASMCs by suppressing M2-macrophage activation. Conclusion: Donepezil could prevent pulmonary vascular and RV remodeling, thereby reversing PAH progression. Moreover, enhancement of the parasympathetic activity could reduce the proliferation and promote the apoptosis of PASMCs in PAH by suppressing M2-macrophage activation.

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Dataset Information

Activation of GPER ameliorates experimental pulmonary hypertension in male rats.

Rationale

Objectives

Methods

Measurements and main results

Conclusions

Publications

Activation of GPER ameliorates experimental pulmonary hypertension in male rats.

Similar Datasets

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