Sex chromosome mechanisms in cardiac development and disease

Abstract

Many human diseases, including cardiovascular disease, show differences between men and women in pathology and treatment outcomes. In the case of cardiac disease, sex differences are exemplified by differences in the frequency of specific types of congenital and adult-onset heart disease. Clinical studies have suggested that gonadal hormones are a factor in sex bias. However, recent research has shown that gene and protein networks under non-hormonal control also account for cardiac sex differences. In this review, we describe the sex chromosome pathways that lead to sex differences in the development and function of the heart and highlight how these findings affect future care and treatment of cardiac disease.

Figure 1.. The Four Core Genotypes and XY* mouse models.

In FCG mice (top), the Y⁻ chromosome is deleted for the testis-determining gene Sry. An Sry transgene (TG) is inserted onto autosome 3 (A3), which is segregates independently from the sex chromosomes. Mating XY males with XX females produces four genotypes: XY with testes and Sry, XY with ovaries without Sry, XX with testes and Sry, and XX with ovaries without Sry The comparison of same-gonad XX and XY mice provides a contrast between mice with high (XX) vs. low (XY) expression of genes that escape X inactivation (“escapees”), and no (XX) vs. some (XY) expression of non-Sry Y genes. Numerous disease models show a sex chromosome effect on cardiovascular and related diseases (ischemia / reperfusion (I/R) injury , pulmonary and systemic hypertension , altherosclerosis , aortic pathologies such as aneurysms , stroke in aged animals , and the amount of body fat . In XY* mice, an aberrant pseudoautosomal region (PAR) on the Y* chromosome leads to unusual recombination with the X chromosome, producing four genotypes on a C57BL/6J background. The minute Y*^X chromosome is nearly equivalent to a PAR, containing very few X genes. Two genotypes (XO, XY) have one X chromosome, and two genotypes (XX, XXY) have two X chromosomes. The level of expression of X escapee genes is a function of number of X chromosomes. When used with the FCG model, the XY* model can determine if a sex chromosome effect is caused by X or Y genes. The model has been used fruitfully in the study of ischemia / reperfusion injury , pulmonary hypertension , aortopathies such as aneurysms , stroke in aged mice , and metabolism and adiposity . NS, not studied.

Figure 1.. The Four Core Genotypes and XY* mouse models.

In FCG mice (top), the Y⁻ chromosome is deleted for the testis-determining gene Sry. An Sry transgene (TG) is inserted onto autosome 3 (A3), which is segregates independently from the sex chromosomes. Mating XY males with XX females produces four genotypes: XY with testes and Sry, XY with ovaries without Sry, XX with testes and Sry, and XX with ovaries without Sry The comparison of same-gonad XX and XY mice provides a contrast between mice with high (XX) vs. low (XY) expression of genes that escape X inactivation (“escapees”), and no (XX) vs. some (XY) expression of non-Sry Y genes. Numerous disease models show a sex chromosome effect on cardiovascular and related diseases (ischemia / reperfusion (I/R) injury , pulmonary and systemic hypertension , altherosclerosis , aortic pathologies such as aneurysms , stroke in aged animals , and the amount of body fat . In XY* mice, an aberrant pseudoautosomal region (PAR) on the Y* chromosome leads to unusual recombination with the X chromosome, producing four genotypes on a C57BL/6J background. The minute Y*^X chromosome is nearly equivalent to a PAR, containing very few X genes. Two genotypes (XO, XY) have one X chromosome, and two genotypes (XX, XXY) have two X chromosomes. The level of expression of X escapee genes is a function of number of X chromosomes. When used with the FCG model, the XY* model can determine if a sex chromosome effect is caused by X or Y genes. The model has been used fruitfully in the study of ischemia / reperfusion injury , pulmonary hypertension , aortopathies such as aneurysms , stroke in aged mice , and metabolism and adiposity . NS, not studied.

Figure 2.. Cardiac tissue in mouse is specified, determined, and forms a beating heart before the differentiation of bipotential gonads into a testis or ovary.

Relative time scale of heart and gonadal development in the mouse. The heart is formed from two populations of cells that give rise to defined structures in the adult heart, the First Heart Field (FHF) which gives rise to the left ventricle (LV) and the Second Heart Field (SHF) which gives rise to the right ventricle (RV) and outflow tract (OFT).

Figure 3.. Genes or genes coding for proteins on the X-chromosome that display male-female differences in cardiac expression.

Genes reported to show male-female differential expression at the mRNA or protein level in adult mouse hearts mapped onto the human X-chromosome ^,,.

Figure 4.. Potential mechanisms of post-transcriptional regulation associated with cardiac male-female sex differences.

Recent studies have implied that post-transcriptional mechanisms are main contributors to male-female differences during embryogenesis and in the adult heart. Studies have implied prospective post-transcriptional mechanisms which include male-female age-related changes in cardiac splicing and exon usage , sex differences in the 5’-UTRs of cardiac mRNAs ^–, and alternative sex transcriptional start sites or alternative polyadenylation .