Xiaowu Wang1, Linhe Lu1, Yanzhen Tan1, Liqing Jiang1, Minggao Zhao2, Erhe Gao3, Shiqiang Yu1, Jincheng Liu4. 1. Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, PR China. 2. Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, PR China. 3. Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA. 4. Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, PR China. Electronic address: labaniz@fmmu.edu.cn.
Abstract
AIMS: Estrogen plays an important role in cardioprotection. Animal experiments showed that the G-protein coupled estrogen receptor 30 (GPR30) specific agonist G1 could reduce post-ischemic dysfunction and inhibit cardiac fibroblast proliferation. However, the underlying mechanism of action is not clear. The current study tests the hypothesis that GPR30 reduces myocardial infarct area and fibrosis in female ovariectomized (OVX) mice by activating the PI3K/AKT pathway. MAIN METHODS: In this study, we established a myocardial infarction (MI) animal model derived from OVX C57BL/6 female mice, and investigated the effect of G1 on cardiac function by echocardiography and Hemodynamics, morphology and expression of fibrosis-related and apoptosis-related proteins by Masson's trichrome and H&E, Immunofluorescence, Western blotting and TUNEL. KEY FINDINGS: Combination with OVX significantly increased myocardial fibrosis and MI area compared to MI treatment alone, as determined by echocardiography and hemodynamics. Further addition of G1 changed the expression of apoptosis-related proteins, decreased the levels of tumor necrosis factor-α and interleukin-10, and reduced the degree of myocardial fibrosis and myocardial infarct area. Primary cultured cardiac fibroblasts (CFs) were subjected to hypoxia/serum deprivation (H/SD) simulating the in vivo ischemia model. When the PI3K/AKT pathway was inhibited by wortmanin in H/SD CFs, G1 failed to induce significant changes in the expression of apoptosis-related proteins. SIGNIFICANCE: It suggested that GPR30 may improve cardiac function in female OVX mice by activating the PI3K/AKT pathway and reducing myocardial infarct size and fibrosis.
AIMS: Estrogen plays an important role in cardioprotection. Animal experiments showed that the G-protein coupled estrogen receptor 30 (GPR30) specific agonist G1 could reduce post-ischemic dysfunction and inhibit cardiac fibroblast proliferation. However, the underlying mechanism of action is not clear. The current study tests the hypothesis that GPR30 reduces myocardial infarct area and fibrosis in female ovariectomized (OVX) mice by activating the PI3K/AKT pathway. MAIN METHODS: In this study, we established a myocardial infarction (MI) animal model derived from OVX C57BL/6 female mice, and investigated the effect of G1 on cardiac function by echocardiography and Hemodynamics, morphology and expression of fibrosis-related and apoptosis-related proteins by Masson's trichrome and H&E, Immunofluorescence, Western blotting and TUNEL. KEY FINDINGS: Combination with OVX significantly increased myocardial fibrosis and MI area compared to MI treatment alone, as determined by echocardiography and hemodynamics. Further addition of G1 changed the expression of apoptosis-related proteins, decreased the levels of tumor necrosis factor-α and interleukin-10, and reduced the degree of myocardial fibrosis and myocardial infarct area. Primary cultured cardiac fibroblasts (CFs) were subjected to hypoxia/serum deprivation (H/SD) simulating the in vivo ischemia model. When the PI3K/AKT pathway was inhibited by wortmanin in H/SD CFs, G1 failed to induce significant changes in the expression of apoptosis-related proteins. SIGNIFICANCE: It suggested that GPR30 may improve cardiac function in female OVX mice by activating the PI3K/AKT pathway and reducing myocardial infarct size and fibrosis.
Authors: Jaqueline S da Silva; Tadeu L Montagnoli; Bruna S Rocha; Matheus L C A Tacco; Sophia C P Marinho; Gisele Zapata-Sudo Journal: Int J Mol Sci Date: 2021-01-07 Impact factor: 5.923