11:50pm Thursday 09 July 2020

Jekyll-and-Hyde molecules play a key role in heart health

Rolf BodmerBut scientists now recognize that moderate amounts of these oxygen-containing molecules are important for cellular communication and normal cellular processes. Nonetheless, it has been unclear how ROS signaling between cells regulates tissue function. In a study published March 20 in Cell Reports, a team spearheaded by Sanford-Burnham researchers revealed how ROS signaling coordinates the activity of different cell types to control heart function in the fruit fly.

Rolf Bodmer, Ph.D., explores the heart’s communication requirements

“Our results shed light on not only ROS signaling, but also cell-to-cell communication in the heart and potentially other tissues,” said senior study author Rolf Bodmer, Ph.D., professor and director of the Development, Aging, and Regeneration Program and adjunct professor of Pediatrics and Pathology at the University of California, San Diego.

Multifaceted molecules

ROS are formed as a natural byproduct of the normal metabolism of oxygen. However, during times of environmental stress, such as ultraviolet or heat exposure, ROS levels can increase dramatically, resulting in significant damage to cell structures. With regard to ROS’ role in cell signaling and homeostasis, studies have traditionally focused on ROS production and the subsequent effects that occur within an individual cell.

But recent evidence suggests that ROS generated in one cell can diffuse into neighboring cells and alter their behavior. For example, in response to tissue damage, the ROS molecule hydrogen peroxide diffuses from the wound into nearby immune cells to direct them to the site of injury. “In our study, we discovered a novel mechanism of ROS signaling that does not involve diffusion between cells,” Bodmer said.

ROS foster a healthy heart

The human heart consists of muscle cells and non-muscle cells that must communicate with each other for the heart to grow, develop, and function normally. Moreover, moderate levels of ROS are important for heart growth and function. But it has been unclear how different types of heart cells interact, and whether ROS play a role in cell-to-cell communication in the heart. To address these questions, Bodmer and his team investigated the potential role of ROS signaling between heart-muscle cells called cardiomyocytes, which regulate heart contraction, and surrounding non-muscle cells called pericardial cells in Drosophila. Drosophila—or fruit flies—are the most widely used organism for biological research, particularly in genetics and devleopmental biology.

The researchers found that pericardial cells in Drosophila contained higher levels of ROS compared with cardiomyocytes. Instead of diffusing between these cells, ROS activated the MKK3-p38 signaling pathway—previously implicated in stress responses—within pericardial cells. Genetic experiments revealed that activation of this signaling cascade in pericardial cells, but not cardiomyocytes, during development was crucial for maintaining normal heart size and establishing normal heart rhythms in adulthood.

Mysterious mechanisms

The findings clearly demonstrate that ROS signaling in pericardial cells influences the function of cardiomyocytes, but it’s still not known exactly how this happens. Bodmer and his collaborators plan to address this question in future studies. They will focus on two candidate mechanisms involving the extracellular matrix (ECM)—the structural support system that surrounds cells and holds them together—and cell-adhesion molecules, which are cell-surface proteins that mediate binding between cells as well as cell-ECM interactions. These potential mechanisms are promising because ROS are known to affect the levels of ECM proteins and cell-adhesion molecules in blood vessels.

Clinical impact

Beyond providing fundamental biological insights into ROS signaling and heart function, the study could have important clinical implications. ROS and p38 signaling pathways exist in a range of organisms including mammals, so the findings are expected to translate to humans. Moreover, ROS from non-myocardial cells may contribute to the aging process in the heart, as well as arrhythmias, congenital heart disease, and other diseases affecting the human heart. “Our study should encourage more research into how one can manipulate the amount of ROS in and around the mammalian heart as a therapeutic avenue to treat these conditions and achieve optimal heart health,” Bodmer said.

A link to the paper can be found at: http://download.cell.com/cell-reports/pdf/PIIS2211124714001430.pdf?intermediate=true

Blog post by Janelle Weaver, a freelance science writer

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