Researchers seek treatments for adult and congenital diseases.
In a study published online Aug. 14 in the Journal of the American College of Cardiology, researchers at the Cincinnati Children’s Heart Institute 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 undergoing reparative surgery.

The experimental approach focuses on the role of the proteins Gbetagamma 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, according to study authors. Their data show that chronic over stimulation of the system (which happens after a heart attack) prompts hypertrophy. 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 Gbetagamma–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,” said Burns Blaxall, PhD, senior investigator and the heart institute’s director of translational science. “Not only has our study identified the cardio–protective properties of pharmacological and fibroblast–specific Gbetagamma–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.”

As they continue their research, the authors are working with collaborators at other institutions to develop a pharmacologic compound that would work much the same way as gallein and also would be safe in animal testing and eventually patients.

Also, because the therapeutic approach tested in the current study may target molecular pathways that affect fibrosis in general, the researchers plan to extend their findings to the study of fibrotic remodeling in other tissues such as the lung, liver, and kidney.