Fibrosis is one of the characteristics of old tissue, a disarraying of the normal processes of regeneration and tissue maintenance that leads to the formation of scar-like structures and consequent loss of tissue function. This is especially notable in the heart, in the kidneys, and in some lung conditions. Little progress was made towards effective therapies until it was determined that senescent cells in old tissue are an important cause of fibrosis; the various therapies under development that target and remove these cells should prove useful in this regard. This isn't the only line of research that might prove viable enough to make a meaningful difference, however. Here, researchers report on continued efforts to sabotage fibrosis via the GRK2 protein and its interactions.
Researchers report encouraging preclinical results as they pursue elusive therapeutic strategies to repair scarred and poorly functioning heart tissues after cardiac injury. They inhibited a protein that helps regulate the heart's response to adrenaline. This alleviated the disease processes in mouse models of human heart failure, and in cardiac cells isolated from heart failure patients. The experimental approach focuses on the role of the proteins Gβγ and GRK2, which are involved in a signaling pathway activated by adrenaline stimulation. The adrenergic system plays a fundamental role in maintaining normal heart function. Data shows that chronic over stimulation of the system (which happens after a heart attack) prompts hypertrophy - a thickening and enlargement of the heart muscle. It also causes fibrosis, the formation of scar tissue.
In a mouse model that closely simulates the disease progression in humans after a heart attack, the researchers blocked Gβγ-GRK2 molecular signaling with an experimental small molecular inhibitor called gallein. When treatment was started one week after the initial cardiac injury, it preserved heart function and reduced tissue scarring and enlargement - essentially rescuing the animals from heart failure. The authors also reported a similar level of protection in a new genetically altered mouse model in which GRK2 is removed from a specific cell type in the heart - the cardiac fibroblast. "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."
Researchers first tested the compound gallein by administering it one week following cardiac injury in control mice with unaltered expression of GRK2. Four weeks after the initial cardiac injury, control mice showed signs of significant fibrosis and heart dysfunction, although targeted Gβγ-GRK2 inhibition with gallein offered the animals substantial cardiac functional protection. This included preservation of the heart muscle's contractile abilities and a reduction of fibrosis within the cardiac tissue. In a second group of mice, the team genetically removed the GRK2 protein shortly after cardiac injury from cardiomyocytes, the contractile/functional cells of the heart. In mice that had GRK2 specifically removed from their cardiomyocytes post-injury, gallein treatment demonstrated significant protection of heart function in the animals. This suggests a potential protective role for the drug beyond cardiomyocyte cells.
In a third group of mice, GRK2 expression was eliminated post injury from just heart fibroblast cells. These animals maintained nearly normal heart function and showed significant improvements in ejection fraction (how forcefully the heart muscle pumps blood) with no further cardiac protection provided by gallein treatment. Researchers attribute the benefits of Gβγ-GRK2 inhibition to a decrease in the pathologic activation of cardiac fibroblasts, as well as a subsequent reduction in fibrosis in the injured cardiac tissue. Taken together, these findings suggest that the improvements observed in the heart's contractile performance after injury may be the result of an overall reduced fibrotic burden.