title: Cardiomyocyte-specific deletion of the G protein-coupled estrogen receptor (GPER) leads to left ventricular dysfunction and adverse remodeling: A sex-specific gene profiling analysis.
abstract: Activation of G protein-coupled estrogen receptor (GPER) by its agonist, G1, protects the heart from stressors such as pressure-overload, ischemia, a high-salt diet, estrogen loss, and aging, in various male and female animal models. Due to nonspecific effects of G1, the exact functions of cardiac GPER cannot be concluded from studies using systemic G1 administration. Moreover, global knockdown of GPER affects glucose homeostasis, blood pressure, and many other cardiovascular-related systems, thereby confounding interpretation of its direct cardiac actions. We generated a cardiomyocyte-specific GPER knockout (KO) mouse model to specifically investigate the functions of GPER in cardiomyocytes. Compared to wild type mice, cardiomyocyte-specific GPER KO mice exhibited adverse alterations in cardiac structure and impaired systolic and diastolic function, as measured by echocardiography. Gene deletion effects on left ventricular dimensions were more profound in male KO mice compared to female KO mice. Analysis of DNA microarray data from isolated cardiomyocytes of wild type and KO mice revealed sex-based differences in gene expression profiles affecting multiple transcriptional networks. Gene Set Enrichment Analysis (GSEA) revealed that mitochondrial genes are enriched in GPER KO females, whereas inflammatory response genes are enriched in GPER KO males, compared to their wild type counterparts of the same sex. The cardiomyocyte-specific GPER KO mouse model provides us with a powerful tool to study the functions of GPER in cardiomyocytes. The gene expression profiles of the GPER KO mice provide foundational information for further study of the mechanisms underlying sex-specific cardioprotection by GPER.
authors.affiliation: Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1009, USA; Internal Medicine/Molecular Medicine, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA. Electronic address: haowang@wakehealth.edu.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1009, USA.
authors.forename: Xuming
authors.initials: X
authors.lastname: Sun
authors.affiliation: Public Health Sciences, Section on Biostatistical Sciences, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Chou
authors.affiliation: Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1009, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Lin
authors.affiliation: Department of Surgery, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA; Department of Internal Medicine/Nephrology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Ferrario
authors.affiliation: Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1009, USA; Institute of Biomedical Sciences, Drug Development Program, Federal University of Rio de Janeiro, Brazil.
authors.forename: Gisele
authors.initials: G
authors.lastname: Zapata-Sudo
authors.affiliation: Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1009, USA; Internal Medicine/Molecular Medicine, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA; Cardiovascular Research Center, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA; Sticht Center on Aging, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina 27157, USA. Electronic address: lgroban@wakehealth.edu.
authors.forename: Leanne
authors.initials: L
authors.lastname: Groban
mesh_terms: D000818:Animals; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D012727:Sex Characteristics; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: C532507:GPER1 protein, mouse; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled
keywords: Cardiomyocyte; GPER; Knockout; Microarray