Researchers at UCLA Health have identified a key gene that may help explain why women are more likely than men to develop a certain type of artery plaque linked to heart disease.
In a study published in Circulation Research, investigators found that a gene known as MYH9 plays an important role in the formation of fibrous plaques. These buildups in the arteries are generally more stable than those more prone to rupture, but they can still lead to heart attacks and other serious cardiac events through plaque erosion.
Atherosclerosis, the buildup of plaque in the arteries, is the underlying cause of most heart disease. Research has mainly focused on unstable plaques, which can rupture and trigger heart attacks. Fibrous, scar-like plaques tend to have thicker caps and different biological characteristics. Although research has shown that women, particularly those under age 50, are more likely to develop these fibrous plaques, the causative mechanisms have remained unclear.
“Although heart disease is the No. 1 killer of women worldwide, taking more women’s lives than all forms of cancer combined, it’s often over
looked or misdiagnosed because symptoms and imaging may not ‘look like’ what we typically see in men’s heart disease,” said Dr. Mete Civelek, a professor and human genetics expert at the David Geffen School of Medicine at UCLA, the article’s corresponding author. “We’ve known that women and men can develop different kinds of plaques in their arteries, but the underlying biology has remained a mystery, which is why we wanted to look more closely at the specific cells that help build and stabilize plaques.”
The international, UCLA-led research team analyzed gene activity in vascular smooth muscle cells – cells that help form and maintain the structure of blood vessels – from more than 150 human donors, 119 males and 32 females. The study identified female-specific gene networks associated with inflammation, cell structure and vascular remodeling.
Vascular smooth muscle cells play an important role in the health of the arteries, but when plaques start to build up, they can switch to a disease state. To observe underlying changes, Civelek and his team isolated cells from the arteries of hearts that were donated for transplantation.
“Using a variety of advanced analytical and computational methods, we compared cells from women and men and looked at how groups of genes work together,” he said. “And we complemented these studies with large human cohort studies that had plaque samples in the Netherlands and Sweden.”
The researchers found two female-biased “gene programs” in vascular smooth muscle cells, one of which pointed strongly to MYH9. Higher levels of MYH9 were linked to plaques with more smooth muscle cells and less fat, which are features of more fibrous plaques. Also, MYH9 was more active in areas of plaque that help form the fibrous cap, the layer that covers the plaque.
The findings suggest that MYH9 may influence how vascular cells respond to their environment, including mechanical stress and biological signals such as hormones, helping to shape plaque structure in a sex-specific way.
“What was especially exciting was that the differences were much clearer when we looked at how genes work together in networks, rather than looking at one gene at a time,” said Civelek, whose lab has focused for years on how genetics and gene regulation shape cardiovascular disease – including differences between women and men. “It was also encouraging that several different kinds of data all pointed to the same gene, MYH9, which makes us more confident that it is biologically important.”
Civelek said the study’s results will not change patient care right away, but they provide a better understanding of the biology of heart disease, especially in women. “In the long run,” he said, “findings like ours will help to develop more personalized ways to predict risk and design treatments that take sex differences into account.”
The investigators said the next step is to understand exactly how MYH9 helps shape plaque biology in women and men differently and to determine if the gene could be useful as a therapeutic target. Additional collaboration is already underway with the lab of Dr. Karen Reue to determine if sex hormones or sex chromosomes are causing sex-specific differences in MYH9 activity. Reue, one of the article’s co-authors, is a professor of human genetics and medicine at the David Geffen School of Medicine at UCLA.
Key Takeaways
• Researchers identified MYH9 as a key gene involved in forming more stable artery plaques in women.
• The study provides new insight into biological differences in heart disease between women and men.
• Findings could support more personalized approaches to cardiovascular treatment and prevention.
