Sex Differences in Cardiac Fibrosis and Hypertrophy
Abstract
Heart disease remains the leading cause of death in men and women. However, prevalence and manifestation differ between sexes. These discrepancies are influenced by underlying hormonal, metabolism, genetic, and molecular differences that lead to different clinical presentation in women. In both genders, cardiovascular disease triggers changes in the heart, which leads to inflammation, fibrosis, and adverse remodeling that may result in hypertrophy or thickening of the walls of the heart. While investigators have studied different types of injury leading to heart failure for many decades, the underlying mechanism remains unknown. Additionally, the nature and severity of heart failure varies in individuals with different genetic background and between sexes. Traditional research studies involve mouse models, since they are easy to handle and manipulate and many types of heart injuries can be experimentally induced. Classical studies normally use a single mouse strain of male gender. This reductionist approach has some limitations, since only a single element can be perturbed at a time to investigate causality. However, considering that presentation of heart failure is variable among people with different genetic background, analysis of a single mouse strain would miss important factors that contribute to the disease. Furthermore, since many studies have been performed in male mice, little is known about the mechanisms that regulate development and progression of scar formation and wall thickening in the female heart after injury. A powerful alternative approach, known as systems genetics, is to study complex traits across populations of humans, integrating clinical genetic differences with gene and protein expression of individual subjects. In this proposal, we take a systems genetics approach to investigate how scar and wall thickening varies among a panel of mice with different genetic background to identify genes that account for differences observed between males and females. Previous studies have highlighted the importance of using this approach in dissecting the genetics of complex traits, such as heart failure and liver disease. A resource termed hybrid mouse diversity panel (HMDP), which includes over 100 strains of inbred mice, has been developed and has been used by many investigators. Several independent investigators have examined how these mice respond to chronic stimulation with a beta-adrenergic drug (isoproterenol) and have highlighted the importance of genetic variation in scar formation and heart wall thickening. In this proposal, we seek to explore sex differences in how isoproterenol infusion can lead to heart fibrosis and remodeling in this genetically diverse panel of mice. We will identify 20 strains that show a wide spectrum of scar formation and wall thickening, from minimal to severe, in the previous study of female mice, and use isoproterenol to induce cardiac hypertrophy in males from these strains. We will then perform imaging studies as well as tissue analysis to determine the variability among the different strains of mice. We will then perform gene expression analysis to identify sex differences in the genes and pathways that regulate scar formation and wall thickening after heart injury. And finally, we will also integrate our results with relevant human systems genetics data. These studies will reveal how female sex across a large panel of mice (that corresponds to human population with different genetic background) impacts development and progression of scar and wall thinking in the injured heart.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110115
Entities
People
- Reza Ardehali
Organizations
- United States Army
- University of California, Los Angeles