Resolving the issue at the “heart”: inflammation and fibrosis in diabetes under the hand of Lipoxin A4

Heart conditions like atherosclerosis, heart attacks and heart failure are the leading killers of people with diabetes, driving a growing global health crisis. Chronic inflammation plays a key role in these heart problems, causing ongoing damage to the diabetic heart over time. Monash University drug discovery researchers have found that a natural fat molecule called lipoxin A4 (LXA4) could significantly reduce inflammation and improve function for diabetic hearts. The preclinical study, published in Cardiovascular Diabetology, found LXA4, which is known for its “calming agent” action in turning off the body’s inflammatory response and preventing chronic inflammation, could also serve as a potential new treatment for diabetes-induced heart disease.

The team observed the beneficial effect of LXA4 on the immune system within the diabetic heart, where molecule stimulate reparative macrophages – a type of white blood cell – within the diabetic heart. These good macrophages reduced scar formation (due to chronic inflammation) in the heart and also helped to improve the overall function. As next steps, efforts to create a stable drug version based on the LXA4 molecule are in progress.  The researchers are also investigating the broader applicability of this study to a range of other inflammatory diseases and exploring other drug options to address different aspects of cardio-pulmonary diseases. These data agrees with others from another scientists team that investigated diabetic phenomena in cardiac fibroblasts.

Cardiac fibroblasts are resident cells of the heart that respond to deleterious stimuli, increasing the synthesis and secretion of both fibrotic and proinflammatory molecules. The molecular mechanisms that regulate inflammation in thse cells are unknown, thus, it is important to find new targets that allow improving treatments for hyperglycemia-induced cardiac dysfunction. NFκB is the master regulator of inflammation, while FoxO1 is a new participant in the inflammatory response, including inflammation induced by high glucose. Scientists at the Faculty of Medicine at the University of Santiago, found that high glucose induces the inflammatory response in cardiac fibrobaslts, using an in vitro and ex vivo model, while FoxO1 inhibition and silencing prevented the effects.

Additionally, LXA4 inhibited the activation of FoxO1 and p65/NFκB, and inflammation of cardiac fibtoblasts induced by high glucose. Therefore, the joint effects of LXA4 on both macrophages and fibroblast could be happen in vivo and therefore FoxO1 and LXA4 could be novel drug targets for the treatment of hyperglycemia-induced inflammatory and fibrotic disorders in the heart, including the common chronic heart failure.

• Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Fu T et al. Cardiovasc Diabetol. 2024 Nov 20; 23(1):413.

González-Herrera F et al. Cell Signal. 2023; 106:110657.

Brennan EP et al. Diabetes. 2018 Dec; 67(12):2657-2667.