Now, the researchers are one step closer to achieving that goal, thanks to their discovery of a key molecule in an unexpected place in heart cells – mitochondria, tiny energy factories that house the controls capable of setting off cells' self-destruct sequence.
The study is the first to identify the molecule, an enzyme known as GRK2 (G protein-coupled receptor kinase 2), in mitochondria. It was led by Walter J. Koch, Ph.D., Professor and Chairman of the Department of Pharmacology at TUSM, and Director of the Center for Translational Medicine at TUSM.
"We have known that GRK2 is involved in the pathological development of certain heart diseases, such as chronic heart failure, and that its increased activity can lead to the death of heart cells. But its mechanism for the latter was unclear," Koch said. In addition, while the enzyme was known to be present in elevated levels in the hearts of patients with heart failure, the reasons for its rise were not fully understood.
Normally, GRK2 hangs out near the plasma membrane of heart cells, where it turns off certain signals transferred from the blood to the tissue. But the researchers at Temple found that it moves to mitochondria in response to two classic features of heart disease, ischemic insult and ensuing oxidative stress. These two processes, in which a momentary lapse in the delivery of oxygen-rich blood to diseased tissues causes a sudden increase in damaging reactive molecules, converge to stimulate the self-destruct program of heart cells. They ultimately cause whole sections of heart tissue to die, leaving behind scars that can severely compromise the ability of the heart to function properly.
Koch's team found that in ischemic heart cells the movement of GRK2 from the cell membrane to mitochondria is chaperoned by a substance called heat-shock protein 90 (Hsp90), which is produced in cells in response to stress. By blocking Hsp90's ability to bind to GRK2, the researchers were able to prevent the enzyme's delivery to mitochondria.
They reached the same result after mutating a residue called Ser670 in the tail end of GRK2's amino acid structure. When the Ser670 residue is activated by a chemical signal, Hsp90 is nudged into action, attaching to GRK2 and carrying it to mitochondria. Mutation of Ser670 also resulted in a wholesale reduction in pro-death signaling in affected heart cells. The effects were observed in human heart muscle cells grown in the laboratory and in mice that had experienced induced heart attacks. The results are detailed in the April 12 issue of the journal Circulation Research.
Koch explained that the translation of the new findings to the clinic, where they would benefit patients, lies in developing new therapeutic approaches that are capable of limiting both the activity of GRK2 and its ability to associate with mitochondria.
"We have a great opportunity here to develop new medicines against heart failure and improve upon this significant disease syndrome," he said. He added that this will take some time but that molecular and pharmacological strategies against GRK2 are in the works. "We are developing a gene therapy tool known as the ßARKct, which is a peptide inhibitor of GRK2, and are quite excited about a clinical trial."Koch and his team have shown in pre-clinical studies that delivery of the ßARKct to failing hearts can inhibit GRK2 and thereby protect the heart from death. In the new study, ßARKct was found to block the enzyme's transit to mitochondria after ischemia, an important step now believed to contribute to the peptide's beneficial effects in heart failure.
What the team uncovers could solidify GRK2 as a key target for therapeutic strategies against heart disease.
Other researchers contributing to the work include Mai Chen at Xijing Hospital, Fourth Military Medical University, Xi'an, China; Shi Pan and Shey-Shing Sheu, at the Center for Translational Medicine at Thomas Jefferson University; and Priscila Y. Sato, Kurt Chuprun, Raymond J. Peroutka, Nicholas J. Otis, Jessica Ibetti, and Erhe Gao at Temple's School of Medicine.
The research was supported in part by NIH grants R37 HL061690, R01 HL085503, PO1 HL075443, P01 HL108806, and P01 HL091799.
About Temple Health
Temple Health refers to the health, education and research activities carried out by the affiliates of Temple University Health System and by Temple University School of Medicine.
Temple University Health System (TUHS) is a $1.4 billion academic health system dedicated to providing access to quality patient care and supporting excellence in medical education and research. The Health System consists of Temple University Hospital (TUH), ranked among the "Best Hospitals" in the region by U.S. News & World Report; TUH-Episcopal Campus; TUH-Northeastern Campus; Fox Chase Cancer Center, an NCI-designated comprehensive cancer center; Jeanes Hospital, a community-based hospital offering medical, surgical and emergency services; Temple Transport Team, a ground and air-ambulance company; and Temple Physicians, Inc., a network of community-based specialty and primary-care physician practices. TUHS is affiliated with Temple University School of Medicine.
Temple University School of Medicine (TUSM), established in 1901, is one of the nation's leading medical schools. Each year, the School of Medicine educates approximately 840 medical students and 140 graduate students. Based on its level of funding from the National Institutes of Health, Temple University School of Medicine is the second-highest ranked medical school in Philadelphia and the third-highest in the Commonwealth of Pennsylvania. According to U.S. News & World Report, TUSM is among the top 10 most applied-to medical schools in the nation.
Jeremy Walter | EurekAlert!
Team discovers how bacteria exploit a chink in the body's armor
20.01.2017 | University of Illinois at Urbana-Champaign
Rabies viruses reveal wiring in transparent brains
19.01.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
20.01.2017 | Awards Funding
20.01.2017 | Materials Sciences
20.01.2017 | Life Sciences