Researchers at the Cincinnati Children’s Heart Institute have inhibited a protein that helps regulate the heart’s response to adrenaline. This alleviated pathological processes in murine models of human heart failure and in cardiac cells isolated from patients with heart failure who underwent reparative surgery. Researchers report encouraging preclinical results while pursuing elusive therapeutic strategies to repair healed and malfunctioning cardiac tissues after cardiac injury – by describing an experimental molecular treatment for heart failure. The experimental approach focuses on the role of Gβγ subunits and GRK2 proteins, which are involved in a signaling pathway activated by adrenal stimulation. The adrenergic system plays a fundamental role in the maintenance of normal cardiac function and the overstimulation of the system (which occurs after a heart attack) induces ventricular hypertrophy – a thickening and enlargement of the heart muscle. It also causes fibrosis, the formation of scar tissue. In a mouse model that closely mimics the progression of the disease in humans after an infarction, the researchers blocked the molecular Gβγ-GRK2 signaling with a small experimental molecular inhibitor called gallein.
When treatment started one week after the initial cardiac injury, it retained cardiac function and reduced scarring and tissue enlargement – essentially saving animals from heart failure. The authors also reported a similar level of protection in a new genetically modified mouse model in which GRK2 is removed from a specific type of cells in the heart: cardiac fibroblast. “Unfortunately, there are essentially no clinical interventions that effectively target these tissue-damaging cardiac fibroblasts – this work can provide evidence that shifts the way we think about treating heart failure,” said Burns Blaxall, PhD, researcher senior and director of the cardiac translational science institute. “Not only did our study identify the cardio-protective properties of pharmacological inhibition of the Gβγ-GRK2 and fibroblastic-specific pathway in a clinically relevant laboratory model, we also demonstrated that inhibition reduced the activation of cardiac fibroblasts by human heart failure, responsible for scarring of heart tissue”.
Heart muscle diseases are common disorders in both the pediatric and adult populations, and the Blaxall group’s research has revealed that many are linked to heart fibrosis. Adult congenital heart disease is also a growing concern for Cincinnati Children doctors and researchers, who are developing new clinical and research strategies for adults who were pediatric cardiopaths. Despite the current promising preclinical results of the study, the authors point out that it is too early to say whether the data will result in clinically beneficial treatments for patients with human heart failure. However, the data open the door to the development of new pharmacological compounds with therapeutic potential. Blaxall and colleagues have spent many years researching clinically relevant clues to address the lack of effective drugs. In 2006 he was on a research group that published results (Journal of Cardiac Failure) that identified elevated levels of GRK2 in cardiac cells from patients with heart failure. The study has put a number of different investigative teams on the trail of exploring whether targeted Gβγ inhibition and its interaction with GRK2 could be a viable solution to the problem. The Blaxall team has published numerous studies that test the therapeutic efficacy of the experimental compound gallein (a Gbetagamma-GRK2 inhibitor) in various animal models of heart failure.
In the present study, the researchers first tested the compound gallein by administering it one week after cardiac damage in control mice with unchanged expression of GRK2. Four weeks after the initial cardiac damage, the control mice showed signs of significant fibrosis and cardiac dysfunction, although the targeted inhibition of Gβγ-GRK2 with gallein offered substantial functional cardiac protection to the animals. This included the retention of contractile abilities of the heart muscle and a reduction of fibrosis in the heart tissue. In a second group of mice, the Blaxall team genetically removed the GRK2 protein shortly after cardiac damage from both cardiomyocytes (the contractile / functional cells of the heart). The study authors note that in mice that had GRK2 specifically removed from their post-injury cardiomyocytes, gallein treatment demonstrated significant protection of cardiac function in animals. This suggests a potential protective role for the drug beyond the cardiomyocytic cells.
In a third group of mice, the expression of GRK2 was eliminated just after a cardiac fibroblast cell injury. These animals maintained almost normal cardiac function and showed significant improvements in the ejection fraction (the force with which the heart muscle pumps the blood) without additional cardio protection provided by gallein treatment. The researchers attribute the benefits of inhibition of Gβγ-GRK2 to a decrease in pathological activation of cardiac fibroblasts, as well as to a subsequent reduction of fibrosis in wounded cardiac tissue. Taken together, these results suggest that the observed improvements in contractile performance of the heart after injury may be the result of a reduced overall fibrotic load. While they continue their research, the authors are collaborating with other institutions to develop a pharmacological compound that would work in the same way as gallein and which would also be safe in animal tests and (possibly) in patients. Moreover, since the therapeutic approach tested in the present study can address the molecular pathways that influence fibrosis in general, the researchers intend to extend their findings to the study of fibrotic remodeling in other tissues such as lung, liver and kidney.
Collectively, these previous studies revealed that the compound has a significant promise for the treatment of cardiac dysfunction and fibrosis. Until the current study, the cellular processes responsible for the reduction of fibrosis have remained unknown – an important knowledge needed to develop new potential drugs.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Travers JG et al. J Am Coll Cardiol. 2017 Aug 22; 70(8):958-971.
Bernardo BC, Blaxall BC. Heart Lung Circ. 2016 May;25(5):425-34.
Piao L, Fang YH et al. Circulation 2012 Dec 11; 126(24):2859-69.
Casey LM et al., Blaxall BC. Circ Res. 2010 Aug 20; 107(4):532-39.