Male-female differences in heart disease could start before birth
Male and female mice during the earliest embryonic stage

Date:
October 20, 2021
Source:
University of North Carolina Health Care
Summary:
New research suggests that male-female differences in protein
expression occur immediately after embryonic cells become heart
cells called cardiomyocytes. This is the earliest stage of heart
development, well before the embryo is exposed to sex hormones.



FULL STORY ========================================================================== Males and females differ in prevalence, treatment responses, and
survival rates for a variety of diseases. For cardiac disease, women
almost uniformly fare far worse than men. There are likely 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 cells
before we're even born.


========================================================================== Published in the journal Development 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 of 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 research of cardiac disease and treatment, as well as advancing the biological study of sex differences in this burgeoning field.

"Our studies show that sex biases in heart development occurs prior
to primary sex determination and can be, and are, associated with sex
bias congenital heart disease," said co-senior author Frank Conlon,
PhD, professor of genetics and biology at the University of North
Carolina at Chapel Hill. "Since sex disparities have been reported in
many other disease states, including cancer, dementia, chronic kidney
disease, obesity, autoimmune disease, and COVID19, our studies provide
a framework for uncovering the mechanisms and pathways of these disease
states, as well." This research was a collaboration between Conlon lab
at the UNC School of Medicine, and the lab of co-senior author is Ileana Cristea, PhD, the Henry L.

Hillman Professor of Molecular Biology at Princeton.

Such health disparities between males and females have been known for a
long time and led to "The Report of the National Heart, Lung, and Blood Institute Working Group on Sex Differences Research in Cardiovascular
Disease" in 2016.

Although sex plays a critical role in cardiac disease, the mechanisms underlying sex differences in cardiac health and disease have been
unknown.

Co-first authors Wei Shi, PhD, a postdoctoral researcher in the Conlon
lab, and Xinlei Sheng, PhD, a postdoctoral researcher in the Cristae lab,
led a systems- based approach to identifying the molecular differences,
at both the RNA and protein levels of cells, between male and female
embryonic and adult hearts in mice. They leveraged the power of the Collaborative Cross (CC) as a surrogate for human diversity, identifying
the proteins, protein complexes, and protein pathways that are common
between mammals and those that diverge between males and females. The
CC is composed of eight founding strains of genetically diverse mice
to address the many research shortcomings in most other available
mouse-strain resources, including small numbers of strains, limited
genetic diversity, and a less than ideal population structure.

Conlon's team then defined the 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 discovered that male-female cardiac
sex differences are not solely controlled by hormones but also through
a sex chromosome mechanism independent of sex hormones," said Conlon,
who is also a member of the UNC McAllister Heart Institute. "Our analysis showed that protein expression differs between male and female hearts at
the embyronic period prior to primary sex determination and prior to the
embryo being exposed to sex hormones." Understanding the basic biology of heart development at this very early stage provides crucial information
for stem cell biologists interested in using cardiac progenitor cells
for regeneration of heart tissue and other cardiac replacement therapies.

========================================================================== Story Source: Materials provided by
University_of_North_Carolina_Health_Care. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Wei Shi, Xinlei Sheng, Kerry M. Dorr, Josiah E. Hutton, James
I. Emerson,
Haley A. Davies, Tia D. Andrade, Lauren K. Wasson, Todd M. Greco,
Yutaka Hashimoto, Joel D. Federspiel, Zachary L. Robbe, Xuqi Chen,
Arthur P.

Arnold, Ileana M. Cristea, Frank L. Conlon. Cardiac proteomics
reveals sex chromosome-dependent differences between males and
females that arise prior to gonad formation. Developmental Cell,
2021; DOI: 10.1016/ j.devcel.2021.09.022 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211020135840.htm

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