A new study Published on Science Advances shows that female and male hearts respond differently to the stress hormone norepinephrine. The mouse study could have implications for i human heart ailments such as arrhythmias and heart failure and how different genders respond to medications.
Noradrenaline: here are its effects
The team built a new type of fluorescence imaging system that allows them to use light to see how a mouse’s heart responds to hormones and neurotransmitters in real time. The mice were exposed to norepinephrine, also known as norepinephrine. Norepinephrine is both a neurotransmitter and a hormone associated with the body’s “fight or flight” response.
The results reveal that the hearts of male and female mice respond uniformly initially after norepinephrine exposure. However, some areas of the female heart return to normal faster than the male heart, which produces differences in the heart’s electrical activity.
“The differences in electrical activity that we observed are called repolarization in female hearts. Repolarization refers to how the heart resets itself between each heartbeat and is closely linked to some types of arrhythmias,” said Jessica L. Caldwell, first author of the study. Caldwell is a postdoctoral scholar in the Department of Pharmacology at the UC Davis School of Medicine.
“We know there are sex differences in the risk for some types of arrhythmias. The study reveals a new factor that may contribute to the different susceptibility to arrhythmias between men and women,” Caldwell said.
Heart disease is the leading cause of death for both men and women in the United States. It accounted for approximately 1 in 4 male deaths and 1 in 5 female deaths in 2020. Despite the impact on both genders, cardiology research has largely been performed on male subjects.
In this study, researchers were interested in examining factors that may contribute to arrhythmias. Arrhythmias are a type of heart disorder in which the electrical impulses that control heart beats don’t work properly. They affect somewhere between 1.5% and 5% of the population.
The new imaging system uses a mouse, called the CAMPER mouse, which has been genetically engineered to emit light during a very specific chemical reaction in the heart: binding to cAMP.
The cAMP molecule (an abbreviation of cyclic adenosine 3′,5;-monophosphate) is an intermediate messenger that transforms signals from hormones and neurotransmitters, including norepinephrine, into action by heart cells.
The light signals of the CAMPER mouse are transmitted by a biosensor using fluorescence resonance energy transfer (FRET). This FRET signal can be detected at high speed and high resolution by a new imaging system specially designed for hearts. This allows researchers to record the heart’s reaction to norepinephrine in real time, along with changes in electrical activity.
This novel imaging approach revealed differences in the breakdown of cAMP in male and female mice and associated differences in electrical activity. After exposure to norepinephrine, cAMP (cyclic adenosine 3′,5;-monophosphate) in the heart increases. However, the bottom part of the heart, the apex, returns to normal more quickly in females than in males. The findings may have implications for heart disorders such as arrhythmias.
The researchers hadn’t planned to study responses based on sex, according to Crystal M. Ripplinger, the study’s senior author. But the researchers started to see a pattern of different reactions, leading them to realize that the differences were based on gender.
Ripplinger, an electrical and biomedical engineer, is a professor in the Department of Pharmacology.
When he started his lab at the UC Davis School of Medicine over a decade ago, he used exclusively male animals. This was the norm for most research at the time. But several years ago, she began including male and female animals in her studies.
“Sometimes the data between the two sexes are the same. But if the data starts to show variation, the first thing we do is look at gender differences. Using male and female mice revealed hints of differences we would never have suspected. Researchers are realizing that it’s not possible to extrapolate to both sexes by studying just one,” Ripplinger said.
Note that with the current study it’s not clear what the differences in cAMP and electrical activity might mean.
“The response in female mice may or may not be protective. But simply documenting that there is a measurable difference in response to a stress hormone is significant. We hope to learn more in future studies,” Ripplinger said.
Other study authors include I-Ju (Eric) Lee, Lena Ngo, Lianguo Wang, Donald M. Bers, Manuel F. Navedo, and Julie Bossuyt of UC Davis; Sherif Bahriz of UC Davis and Mansoura University; Bing (Rita) Xu and Yang K. Xiang of UC Davis and VA Northern California.
Males and females differ in prevalence, treatment responses, and survival rates for a variety of diseases. For heart disease, women fare almost uniformly much worse than men. There are probably many reasons for this, and scientists at the University of North Carolina at Chapel Hill and Princeton University seemed to have found one deep inside our cells before we were even born.
Published in the journal Developmental Cell, this research suggests that male-female differences in protein expression occur immediately after embryonic cells become heart cells called cardiomyocytes. This is the earliest stage in heart development, well before the embryo is exposed to sex hormones.
This comprehensive report is the first to detail the mechanisms of cardiac sex disparities at such an early stage, providing new opportunities for heart disease research and treatment, as well as advancing the biological study of sex differences in this expanding field.
“Our studies demonstrate that sex biases in heart development occur before primary sex determination and can be, and are, associated with sex biased congenital heart disease,” said co-senior author Frank Conlon, Ph.D. ., professor of genetics and biology at the University of North Carolina at Chapel Hill. “Because gender disparities have been reported in many other disease states, including cancer, dementia, chronic kidney disease, obesity, autoimmune diseases, and COVID-19, our studies provide a framework for uncovering the mechanisms and pathways of these disease states. , as well as .”
Such health disparities between males and females have been known for a long time and led in 2016 to the “Report of the National Heart, Lung, and Blood Institute Working Group on Sex Differences Research in Cardiovascular Disease”. disease, the mechanisms underlying sex differences in heart health and disease are unknown.
Co-first authors Wei Shi, Ph.D., postdoctoral researcher in the Conlon lab, and Xinlei Sheng, Ph.D., postdoctoral researcher in the Cristae lab, conducted a systems-based approach to identifying molecular differences , at both RNA and protein levels of cells, between male and female embryos and adult hearts in mice. They harnessed the power of the Collaborative Cross (CC) as a surrogate for human diversity, identifying proteins, protein complexes and protein pathways that are common among mammals and those that diverge between males and females.
The CC is composed of eight genetically diverse mouse founder strains to address the many research deficiencies in most other available mouse strain resources, including small number of strains, limited genetic diversity, and an all-round population structure. other than ideal.
Conlon’s team then defined cell types that express a subset of these proteins to show differences in expression in the cardiomyocyte lineage between male and female hearts.
“Contrary to the current paradigm, we found that male-female cardiac sex differences are not controlled solely by hormones, but also through a sex chromosomal mechanism independent of sex hormones,” said Conlon, who is also a fellow at the UNC McAllister Heart Institute. . “Our analysis showed that protein expression differs between male and female hearts in the embryonic period before primary sex determination and before the embryo is exposed to sex hormones.”
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