Inhibiting a Signaling Pathway May Reduce Fibrosis After a Cardiovascular Event
Treatment with a Gβγ-GRK2 preserved the heart's function after a cardiac injury.
The results of a preclinical trial suggest that a novel method may repair scarred and poorly functioning heart tissue resulting from a cardiac injury. The authors of a study published by the Journal of the American College of Cardiology suggest that inhibiting a pathway may be the key to treating heart fibrosis.
Diseases of the heart muscle are common in children and adults. Prior studies show that many conditions are linked to fibrosis of the heart tissue, making it a clear treatment target.
In both mice and human cardiac cells, blocking a protein that regulates the heart’s response to adrenaline was found to reduce fibrosis.
The novel approach focuses on Gβγ and GRK2 proteins, which are involved in a pathway activated by adrenaline. The adrenergic system plays a crucial role in normal heart function, according to the authors.
The findings show that over-stimulation of the system, which can happen after a heart attack, results in hypertrophy and fibrosis.
In a mouse model that follows the progression after heart attack, the authors blocked Gβγ-GRK2 signaling with gallein, an investigational small molecular inhibitor.
In mice, the drug was started 1 week after cardiac injury, while control mice did not receive treatment. Treatment with gallein was found to preserve heart function and reduce fibrosis and hypertrophy—preventing heart failure—while control mice had significant fibrosis and heart dysfunction after 4 weeks, according to the study.
The authors said these results suggest that gallein protected the heart’s function, including its contractile ability and a reduction in fibrosis.
The investigators also reported similar results in mice engineered to have cariomyocytes without GRK2 shortly following cardiac injury. The authors discovered that these mice benefited from heart function protection.
These results suggest that gallein may have benefits beyond cardiomyocyte cells, according to the study.
In a third group of mice, GRK2 expression was removed in fibroblast cells post-injury. The mice were found to have nearly normal heart function and improved ejection fraction. Interestingly, these animals did not see additional benefits from gallien, according to the study.
The authors believe that the benefits from gallien are due to a reduction in fibroblasts and fibrosis. Overall, the findings suggest that improvements to the heart’s contractile performance may reduce fibrosis risk, according to the study.
Despite showing promise, the authors caution that their findings are preliminary and it is unclear if it will translate into beneficial treatments for patients with heart failure; however, the data may create the opportunity to develop novel drugs for these patients, according to the study.
The authors plan to develop a compound that would be safe for additional animal and patient testing and expand their research to the lungs, liver, and kidneys.
"Regrettably, there are essentially no clinical interventions that effectively target these tissue-damaging cardiac fibroblasts. This work may provide evidence that shifts the way we think about treating heart failure," said senior researcher Burns Blaxall. "Not only has our study identified the cardio-protective properties of pharmacological and fibroblast-specific Gβγ-GRK2 inhibition in a clinically relevant mouse model, we also showed that inhibition reduced the activation of human heart failure cardiac fibroblasts. This is a key cell type responsible for the scarring of heart tissue."