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!
Millions through license revenues
27.04.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn
New High-Performance Center Translational Medical Engineering
26.04.2017 | Fraunhofer ITEM
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
28.04.2017 | Event News
20.04.2017 | Event News
18.04.2017 | Event News
28.04.2017 | Medical Engineering
28.04.2017 | Earth Sciences
28.04.2017 | Life Sciences