There are notable differences between men and women in their susceptibility to many human diseases, including cardiovascular disease. For example, women typically have smaller hearts that pump faster, while men have larger hearts that pump more blood with each heartbeat.
In light of a 2016 report by the National Heart, Lung, and Blood Institute (NHLBI) Working Group on Sex Differences Research in Cardiovascular Disease, researchers have been making massive efforts to understand what, in the underlying biology, predisposes people to sex-specific cardiovascular disease.
Researchers in the laboratories of Frank L. Conlon, PhD, professor of biology and genetics, and Bill Marzluff, PhD, Kenan Distinguished Professor of Biochemistry and Biophysics, have recently made a large stride in the field, uncovering one of the molecular reasons behind sex disparities in heart disease.
In a new study led by graduate student Ike Emerson in the Conlon lab, researchers discovered that a microRNA called miR-871-one of the smallest RNAs found in cells-plays a significant role in the physiological and pathological differences observed between men's and women's hearts. Their findings were published in the most recent issue of Circulation Research.
"The findings demonstrate that miRNAs on the X chromosome can directly control male-female differences in the heart," said Conlon, who is affiliated with the UNC McAllister Heart Institute. "The findings also show that male-female differences in biology can be established after a gene is turned on."
MicroRNAs and Heart Disease
Frank Conlon, PhD
MicroRNAs are small, single-stranded nucleic acids that play a crucial role in regulating gene expression, effectively turning genes down to fine-tune protein production in the body. Although these tasks may seem minor, they significantly influence most bodily functions, from the cellular development of organs to the rhythmic beating of our hearts.
Conlon has dedicated years to researching the early stages of heart development and the differences in heart disease between the sexes. In 2021, Conlon published a paper in Developmental Cell, showing that genes on the X and Y chromosomes act to regulate heart proteins. However, the molecular mechanisms underlying these disparities remain poorly understood.
To fill this gap, Conlon's lab collaborated with Marzluff, an expert in gene regulation by RNAs in animal cells, to catalog all the changes in microRNAs between male and female hearts.
Out of four microRNAs located on the X chromosome, the researchers homed in on miR-871. This microRNA reduces the amount of sarcalumenin or SRL, a protein, produced in the heart. SRL helps the heart cells recharge and reset after each muscle contraction and keeps the heart "in rhythm." MiR-888, the human equivalent of miR-871, similarly regulates SRL levels in the human heart.
Researchers confirmed their findings by manipulating the levels of miR-871. They used genetic techniques to inhibit the production of miR-871 in female mice. This intervention increased SRL levels and improved the heart's ability to recharge between beats. Consequently, the hearts of the female mice began to resemble the beating pattern and functionality of male hearts.
Connections to Recent Nobel Prize
William Marzluff, PhD
Researchers may use this information to develop therapies that modify human microRNA levels to treat heart diseases. MicroRNA-based therapies are already being explored for other conditions.
Marzluff states that their recent findings are especially relevant, given that two researchers, Victor Ambros, and Gary Ruvkun, were awarded the 2024 Nobel Prize in Physiology for their discovery of microRNA function and development in nematodes for their work in the 1990s.
"It is striking that in both mice and humans, the same miRNA binds in two places on the SRL mRNA,", said Marzluff, co-director of the UNC RNA Discovery Center. "This miRNA reduces the ability, but does not totally prevent, the SRL mRNA from synthesizing protein, which is similar to what was found in the initial papers by Ambros and Ruvkun."
Further Research and Potential Treatments
Researchers seek to investigate further the roles of miR-871, miR-888, and other miRNAs in cardiac aging to identify potential therapeutic targets or biomarkers for age-related cardiac diseases. This research could ultimately lead to more personalized treatment strategies that consider sex differences in cardiac health and aging.
The Conlon lab will continue to examine other miRNAs that vary between male and female hearts, focusing on how the affected proteins contribute to physiological differences between the sexes. They are also working to understand why the female heart produces more miRNAs than the male heart.
