CU researchers identify a new pathway for preventing heart fibrosis

researchers in University of Colorado School of Medicine They discovered a new mechanism to slow scarring of heart tissue – a process known as cardiac fibrosis.

“Cardiac fibrosis occurs in response to a variety of stresses,” says the corresponding author of the study. Timothy McKenziePh.D., Professor medicine In the Department of Cardiology. “They can be good. For example, if you have a heart attack and a significant amount of heart muscle dies, you need to replace that muscle with something. In this case, the fibrous scar prevents the heart from rupturing and the person from dying. But we are more interested in pathological fibrosis, It is uncontrolled fibrosis that occurs in a person with long-term high blood pressure or other comorbidities. This can cause hardening of the heart and lead to what is called diastolic dysfunction.”

Unique damper

CU study, Posted today In the American Heart Association’s Journal of Circulation Research, the compound SW033291 is shown to slow fibrosis by inhibiting the action of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that degrades eicosanoids, which are lipid signaling molecules that help prevent fibrosis.

“Chronic fibrosis is thought to be the main factor in causing heart failure,” MacKenzie says. Heart failure affects millions of people worldwide, and there are no good treatments for preventing or reversing heart failure. That’s why we started these studies.”

Show efficacy in human samples

Mackenzie and his research team began their study by performing a high-throughput phenotyping assay using a number of compounds, looking to prevent activation of fibroblasts, the cells responsible for driving fibrosis.

They collided with nine small molecules that have the combined ability to block the activation of heart, lung, and kidney fibroblasts. Of these nine, the compound SW033291 seemed the most promising.

In addition to lab tests and animal models, the UCLA researchers worked with Michael BristowMD, PhD, professor of cardiology, and Amrut Ambardikar, MD, associate professor of cardiology, and their teams to create a new biobank of failing human cardiac fibroblasts taken from patients receiving heart transplants, as well as non-failing cardiac fibroblasts from control donors. SW033291 showed a remarkable ability to reverse the active state of failure in human cardiac fibroblasts, McKenzie says, supporting the idea that inhibition of 15-PGDH could be useful for relieving existing cardiac fibrosis in patients.

next steps

As their research continues, Mackenzie and his team plan to focus on the roles of 15-PGDH in various cell populations, including fibroblasts, immune cells, and cardiomyocytes. They also want to conduct additional efficacy studies with SW033291, testing it in more severe models of heart fibrosis and diastolic dysfunction.

Mackenzie says the group also plans to look more closely at the functions of different eicosanoids in inhibiting fibroblast activation, and how they activate signaling pathways to prevent fibroblasts from causing fibrosis.

“This research led to the identification of a new pathway that regulates cardiac fibrosis,” he says. “No one has studied 15-PGDH in the heart. This opens up a whole new area of ​​investigation and suggests ways to target fibrosis in the heart to treat a wide number of heart conditions, including heart failure.”

This work was supported in part by
Fibrosis and Translation Research Consortium, a program funded by the CU School of Medicine and co-administered by McKinsey. It aims to improve understanding of fibrotic diseases across different organ systems.

In addition to McKinsey, Bristow, and Ambardekar, other study researchers are Maria Kavasin, PhD, an instructor in cardiology. former UCSD faculty member Keith Koch, Ph.D.; Postdoctoral fellows Marcelo Rubino, Ph.D., Joshua Travers, Ph.D., and Marina Felispino, Ph.D.; and professional research assistants Alaina Headrick, Blake Enyart, Jessica Schwisow, Elizabeth Hardy, MS, Keenan Kaltenbacher, and Eric Jonas, as well as Madeleine Lemieux, PhD, from data analytics firm Bioinfo.

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