New research has confirmed that the presence of XX sex chromosomes increases the amount of fat circulating in the blood, which leads to narrowing of the arteries and ultimately a higher risk of heart attacks and coronary artery disease. The research was published in Nature Communications.
The leading cause of death in women is coronary artery disease (CAD), but women develop CAD almost 10 years later than men. For many years, scientists attributed this decade-long delay in disease development to the protective effects of sex hormones. There is a lot of evidence that hormones like estrogen and progesterone protect the heart, but scientists had little data on the influence of the genetic component--the X chromosome--on the heart.
A team set out to understand the role of sex chromosomes in the cardiovascular system. The team studies chromosome effects in mice, and for this most recent discovery they were able to zero in on XX chromosomes by removing hormones.
The authors used mouse models to separate effects of sex chromosomes and hormones on atherosclerosis, circulating lipids and intestinal fat metabolism. They assessed atherosclerosis in multiple models and experimental paradigms that distinguish effects of sex chromosomes, and male or female gonads.
According to the paper's first author, if the levels of circulating lipids transported by the blood are too high, they will start to accumulate in and on the artery wall, leading to plaque buildup. These plaques harden and narrow the artery, reducing blood flow to the vital organs.
The team looked at lipids absorbed from the diet and made in the liver. Pro-atherogenic lipids and atherosclerosis are greater in XX than XY mice, indicating a primary effect of sex chromosomes. Small intestine expression of enzymes involved in lipid absorption and chylomicron assembly are greater in XX male and female mice with higher intestinal lipids.
The senior author said, "We looked at how our X sex chromosomes were influencing the levels of lipids in the blood and in the arteries." What they found is that an XX sex chromosome combination promotes efficient use of fat.
Women need fat to bear and feed babies, the senior author explained: "We're set up, potentially through our XX sex chromosomes, so that we can effectively absorb that lipid from the diet and put it into our fat cells and maybe even make it in the liver."
Everything is fine until women hit menopause and the protective effects of hormones disappear, leaving women with what the senior author calls "that XX thrifty, fat-absorbing kind of genotype."
The team is looking at genes that are changed in the liver and in the intestine to find novel targets for drug development. If they can find target genes that influence atherosclerosis, scientists can then explore the effects of existing drugs or develop new ones.
The author that the next step is to study the role of the number of X chromosomes in atherosclerosis. "We don't know if our findings are due to the presence of two X chromosomes or due to the absence of the Y chromosome," the author said.
These findings may also drive choice of diet for post-menopausal women. The senior author said, "For example, if they're very effective fat absorbers, obviously, once they get post-menopausal, they need to be careful about the fat content."
The role of XX chromosomes in heart disease risk in women
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