Article "Mechanistic Pathways of Sex Differences in Cardiovascular Disease by Regit-Zagrosek V and Kararigas G, Charite University, Berlin, Germany."
The objective of this post is to introduce sex hormones and their receptors that play a role in cardiovascular disease (CVD).
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Sex hormones are produced early on in the embryonic development. Different epigenetic and genetic factors play a role in the modifications and organization of sex hormones during development. Sex hormones are part of the endogenous signaling molecules that form the cellular pathways through gene regulation and synthesis.
Sex hormones such as estrogen, progesterone, androgen, and testosterone together or individually play a role in the cardiovascular system. The most prominent type of sex hormones found in cardiomyocytes is estrogen and androgen along with their corresponding receptors.
Testosterone is a natural androgen synthesised in the gonads. The synthesis of testosterone results in an active metabolite called dihydrotestosterone (DHT), which binds to the androgen receptor (AR). When this binding occurs, DHT becomes the most prominent type of androgen in the body and its main role becomes to amplify testosterone-dependent actions and form reproductive organs.
So, how is testosterone relevant when talking about CVD?
DHT is converted from different types of testosterone isoforms 1-3 of the enzyme 5- α -reductase, which are equally expressed in hearts of females and male mice. It has been recently studied that 3 of the enzyme 5-α-reductase (Srd5a3) is the most prominent type of enzyme found in the heart. The expression of all the 5- α -reductase is found to be increased in human and mouse hypertrophic hearts, therefore leading to increased levels of DHT.
In addition to DHT, the most abundant and circulating estrogen is 17-β-estradiol (E2). E2 binds equally to the receptors, ERα and ERβ. E2 is strongly identified among other types of estrogen (e.g., estrone, estriol). E2 is produced as a result of testosterone converting by the enzyme aromatase. The enzyme aromatase is found in a number of extragonadal tissues including the brain, heart, bones and vasculatare in both of the sexes. There has been a correlation between the increase level of aromatase conversion of androgen and estrogen in adipose tissue that has resulted in significant increase in circulating E2. Naturally in men, E2 is produced in large quantities by aromatization of the androgenic precursor from the testes and adrenal glands. In recent literature, it has been found that E2 is abundant in elderly men than elderly women.
So, now that we are familiar with the type of hormones that can be studied for Cardiovascular Disease. How may their relevant receptors play a role in the regulation in the cardiovascular system?
Sex hormones and their activated receptors include the AR, ERα, ERβ, and the G protein-coupled receptor GPR30. These receptors, at both the cellular and sex specific level, affect both genomic and non-genomic pathways. The regulation of these sex hormones in cardiovascular disease is not very well studied, but there is report that these receptors have an inversely affect on cardiovascular disease.
The AR, ERα and ERβ belong to the nuclear steroid hormone receptor family. When activated, these receptors play a role in gene expression in a hormone-dependent fashion. They are constricted of a Zinc finger based DNA-binding domain (DBD) in the C region, which contains a region that mediates dimerization, a COOH terminal lingand binding domain (LBD) located in the E region ( this contains a lingand dependent activation function -AF2) that enhances the binding to specific nucleotide sequences.
Moreover, these receptors contain a NH2-terminal A/B domain with component activation function (AF-1) and a hinge domain ( D region). For more information on the structure of nuclear receptors see the link accompanied by figure 1.
Figure1: http://nptel.ac.in/courses/102103012/module5/lec2/3.html
Numerous polymorphisms of ERα and ERβ have also been identified. These polymorphisms have been localized to specific diseases in the sexes. For example, ERβ polymorphisms are associated with increased Left Ventricular (LV) mass and LV wall thickness and ERα has been correlated with increased risk in myocardial infarction (MI).
Where have these sex receptors been found?
ERα and ERβ have been found to be in the vascular endothelial, vascular smooth muscles, cardiac fibroblasts and cardiac myoctyes of male and female individuals.
ERα mRNA are similarly expressed in the hearts of male and females, while ERβ mRNA levels are higher in the male heart than that of the female. In this article, the authors demonstrated "the involvement of both ERs in human CVD through the upregulation of mRNA levels of both ERα and ERβ in the myocardim of patients with aortic stenosis (AS) and the increase of mRNA and protein levels of ERα in end-stage failing hearts". They observed a significant changes in "the intracellular localization of ERα in failing hearts, away from the interrelated disk, where it is usually found in healthy hearts."
Through studying the mechanistic pathways of the ERS, they
also discovered the involvement of the Nuclear factor kB (NF-kB) pathway ( Nf-kB is a protein complex that controls the transcription of DNA, Cytokine production and cell survival), in regulating the ERα expression in the human heart. In addition to these findings, a pool of ERs is found in the plasma membrane. The ERs localized in the membrane play a role in regulating the extra nuclear activity of E2. There has also been some reports identifying the presence of ERα and ERβ in the mitochondria.
The GPR30 receptor is responsible for binding ER to E2 in a direct manner and it has been mentioned to have ER mediating nongenomic effects of E2. GPR30 has been found in endothelial cells, however its role in mediating E2 has not been fully studied.
These are the main sex hormones that are identified to get us a step closer in understating sex-specific cardiovascular diseases. We can also explore how these sex hormone receptors are manipulated in animal models to get a better understanding of CVD.