Grant: Operating Grant

. In the age of personalized medicine, one of the first distinctions to be made concerns the sex of the patient. Over the last century, men's life expectancy has been consistently shorter than that of women. In subjects ranging from 30 to 64 years of age, the mortality due to cardiovascular diseases is 3 times higher in men than in women. Although sex steroids are commonly thought to be responsible for such differences, the contributions of sex chromosomes have not been explored fully. Chromosome Y (chrY) is the male-specific chromosome. Some studies show that genetic variants of chrY associate with differences in cardiovascular disease characteristics, but the mechanisms responsible for these effects have remained a mystery. We have performed "chrY swapping" experiments where we have compared adult male mice from the C57BL/6J strain to C57.YA mice (i.e. C57BL/6J mice whose original chrY has been replaced with that from the A/J strain). The 2 strains differ in terms of how testosterone affects the size of cardiac cells and how it regulates the expression of several cardiac genes. Moreover, removal of testosterone by castration decreased the expression of genes that are important for cardiac contractility in C57.YA, but not C57BL/6J mice. Of note, reduced serum levels of testosterone in humans are highly prevalent in patients with chronic heart failure, but not all patients benefit equally from testosterone supplementation. Additional experiments have allowed us to better understand the effects of genetic variants of chrY and to uncover novel mechanisms whereby they exert these effects. Altogether, C57BL/6J and C57.YA male mice constitute unique biologic animal models to improve our understanding of the biologic actions of the male-specific chrY. Our proposed comparisons between the 2 strains will allow us to better understand the effects of this chromosome on the heart, as well as some of the male-specific aspects of heart diseases.