Abstract
Estrogen exerts diverse biological effects in multiple tissues in both animals and humans. Much of the accumulated knowledge on the role of estrogen receptor (ER) in the heart has been obtained from studies using ovariectomized mice, whole body ER gene knock-out animal models, ex vivo heart studies, or from isolated cardiac myocytes. In light of the wide systemic influence of ER signaling in regulating a host of biological functions in multiple tissues, it is difficult to infer the direct role of ER on the heart. Therefore, we developed a mouse model with a cardiomyocyte-specific deletion of the ERα allele (cs-ERα−/−). Male and female cs-ERα−/− mice with age/sex-matched wild type controls were examined for differences in cardiac structure and function by echocardiogram and differential gene expression microarray analysis. Our study revealed sex-differences in structural parameters in the hearts of cs-ERα−/− mice, with minimal functional differences. Analysis of microarray data revealed differential variations in the expression of 208 genes affecting multiple transcriptional networks. Furthermore, we report sex-specific differences in the expression of 56 genes. Overall, we developed a mouse model with cardiac-specific deletion of ERα to characterize the role of ERα in the heart independent of systemic effects. Our results suggest that ERα is involved in controlling the expression of diverse genes and networks in the cardiomyocyte in a sex-dependent manner.
Highlights
Estrogen receptors (ER) are involved in multiple biological processes in a variety of tissues including the cardiovascular system, adipose tissue, and sex organs [1]
We report on the generation of mice with cardiomyocyte-specific deletion of ERa
Cs-ERa2/2 mice raised under normal diet in absence of external stress were viable and overtly normal
Summary
Estrogen receptors (ER) are involved in multiple biological processes in a variety of tissues including the cardiovascular system, adipose tissue, and sex organs [1]. The non-genomic actions, on the other hand, are mostly membrane-initiated and involve signaling cascades, such as the mitogen-activated protein kinase (MAPK) pathway, the cyclic adenosine mono-phosphate/protein kinase A (cAMP/PKA) pathway, or the endothelial nitric oxide synthase (eNOS) pathway [4,5,6]. To date, the studies describing the role of ERs on the cardiovascular system were based on whole-body ER knockouts or on the effects of ER ligands, such as estrogen, on the heart, but with the caveat that such ER ligands affect peripheral tissues. In light of the wide influence of ER signaling in regulating physiologic functions in multiple tissues, including systemic energy homeostasis, and considering that peripheral substrates can induce cardio-metabolic remodeling, it is difficult to infer the direct role of ER on the heart using whole-body KO models
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