CU researchers discover a new mechanism for slowing cardiac fibrosis

Researchers at the University of Colorado (CU) have discovered a new mechanism that could significantly slow the progression of cardiac fibrosis. This new finding, published in the journal Cell Reports, represents a major step forward in the treatment of cardiac fibrosis, a disease that can lead to heart failure.

Cardiac fibrosis is a condition in which the heart’s muscle walls thicken and the tissues become stiff. This can lead to a decrease in the organ’s pumping ability, accompanied by a wide range of symptoms, from irregular heartbeat and breathlessness, to arrhythmia and chest pain. It is thought to be caused by unregulated collagen synthesis due to an increase in the activity of the enzyme Rac1.

This is where the CU research team comes in. After researching the structure and regulation of cardiac fibroblasts, they identified a new way to inhibit Rac1. Specifically, they discovered that a compound called granulocyte-colony stimulating factor (G-CSF) could suppress Rac1 activity and therefore help to slow the progression of fibrosis.

In the lab, the researchers found that G-CSF readily reduced the expression of Rac1 in mouse models and human cardiac fibroblasts in culture. They also observed a marked reduction in collagen production and a corresponding increase in the activity of structures known as Z-lines, which are integral to healthy muscle cell function.

In addition, the team saw that G-CSF was able to reverse fibrosis in animal models of the disease. What’s more, the beneficial effects of G-CSF treatment lasted for at least a month – a remarkable finding given the usually progressive nature of fibrosis.

The team’s findings demonstrate that G-CSF could potentially be an effective therapeutic agent for cardiac fibrosis, as it not only suppresses Rac1 activity, but also encourages Z-line formation. Although more clinical studies will be necessary to prove the efficacy of this potential treatment, the findings of the CU researchers represent a major step forward in our understanding of cardiac fibrosis and the opportunities for its treatment.

Researchers at the University of Colorado School of Medicine have discovered a new mechanism for slowing scarring of heart tissue -; a process known as cardiac fibrosis.

Fibrosis of the heart occurs in response to a variety of stresses. It can be good. For example, if you have a heart attack and a significant amount of your cardiac muscle dies, you need to replace that muscle with something. In that case, the fibrotic scar keeps the heart from rupturing and prevents someone from dying. But we’re more interested in pathological fibrosis, which is uncontrolled fibrosis that occurs in someone who has long-standing hypertension or other comorbidities. That can cause stiffening of the heart and lead to something called diastolic dysfunction.”

Timothy McKinsey, PhD, study’s corresponding author, professor of medicine, Division of Cardiology

A unique inhibitor

The CU study, published today in the American Heart Association’s Circulation Research journal, shows that the compound SW033291 slows fibrosis by inhibiting the action of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that degrades eicosanoids, which are lipid signaling molecules that help to prevent fibrosis.

“Chronic fibrosis is thought to be a major player in the pathogenesis of heart failure,” McKinsey says. “Heart failure affects millions of people worldwide, and there aren’t any good therapies to prevent or reverse cardiac fibrosis. That’s why we initiated these studies.”

Showing effectiveness in human samples

McKinsey and his research team started their study by performing phenotypic high throughput screening with a number of compounds, looking to block activation of fibroblasts, the cells responsible for driving fibrosis.

They hit upon nine small molecules that had the common ability to block activation of heart, lung, and kidney fibroblasts. Of those nine, the compound SW033291 seemed the most promising.

In addition to laboratory tests and animal models, the CU researchers worked with Michael Bristow, MD, PhD, professor of cardiology, and Amrut Ambardekar, 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 nonfailing donor control cardiac fibroblasts. SW033291 exhibited a remarkable ability to reverse the activated state of failing human cardiac fibroblasts, McKinsey says, supporting the notion that 15-PGDH inhibition could be useful for ameliorating existing cardiac fibrosis in patients.

Next steps

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

McKinsey 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 has 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 a whole new avenue of investigation and suggests ways to target fibrosis in the heart to treat a plethora of cardiac diseases, including heart failure.”


University of Colorado Anschutz Medical Campus

Journal reference:

Rubino, M., et al. (2022) Inhibition of Eicosanoid Degradation Mitigates Fibrosis of the Heart. Circulation Research.

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