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.

Blunting of estrogen modulation of cardiac cellular chymase/RAS activity and function in SHR

“…Total RNA was isolated from cardiomyocytes using the RNeasy Lipit Tissue Mini Kit (Qiagen, Inc., Germantown, MD) and further purified using RNeasy MinElute Cleanup Kit (Qiagen, Inc., Germantown, MD) followed by quality assessment on an Agilent 2100 bioanalyzer, as previously described (Wang, Sun, et al, ). Relative quantification of mRNA levels by real‐time qPCR for angiotensinogen, renin, ACE, ACE2, chymase, AT1R, AT2R, and Mas was performed using a SYBR Green PCR kit (Qiagen, Inc., Germantown, MD), as previously described (Wang et al, ).…”

GPCRs in context: sexual dimorphism in the cardiovascular system

“…It is unlikely that these discrepancies are due to compensatory increases in the expression of classical ERs, as both Wang et al . () and Martensson et al . () reported no change in mRNA abundance of ERα and ERβ.…”

“…Intriguingly, Wang et al . () report that cardiomyocyte‐specific deletion of GPER causes left ventricular (LV) dysfunction and remodelling in both sexes but a male‐specific inflammatory response. This result is difficult to reconcile with the above studies, which show no deleterious cardiovascular effects in male mice with global GPER gene deletion, especially considering the similar expression of cardiac GPER between the sexes (Deschamps and Murphy, ).…”

Female Heart Health: Is GPER the Missing Link?

“…Elevations in LV filling pressure initially compensate, but eventually pulmonary congestion develops as a result of increased left atrial (LA) pressure (10). While a wide range of diastolic function parameters can be obtained by Doppler-echocardiography (11), a simple composite of blood flow and tissue Doppler measures, as reviewed by ourselves and others (12)(13)(14) can sensitively detect and predict diastolic dysfunction in humans (15)(16)(17), non-human primates (18,19), and preclinical rodent research models (20)(21)(22)(23)(24)(25). The spectrum of diastolic dysfunction is portrayed schematically in Figure 1.…”

“…Initial work showed that administration of the GPER agonist G1 prevents diastolic dysfunction and LV remodeling in OVX (25) and salt-loaded (65) mRen2.Lewis rats. To tease out more precise information about the functional role of GPER in the heart, we generated a novel conditional mouse model where GPER was specifically deleted in cardiomyocytes (23). Therefore, the remainder of the review FIGURE 2 | GPER in the functional circle of diastology of the female heart.…”