Case Western Reserve University School of Medicine researchers have identified a major indicator of two deadly diseases of the heart and blood vessels: heart failure and aortic aneurysm. The absence of the Kruppel-like Factor 15 (KLF15), when combined with stress, leads to both heart failure and aortic aneurysms.
The genetic factor, KLF15, protects the heart and aorta's ability to maintain structural and functional integrity. Patients with these diseases were found to have reduced levels of the protective gene, and in an animal study, the researchers proved that deficiency of this single gene predisposes one to these cardiovascular diseases. Furthermore, they show that KLF15 exerts its protective effects in the heart and aorta through a common molecular mechanism. Lastly, the researchers show that drugs targeting this molecular pathway can be used to treat heart failure and aortic aneurysms. The unprecedented findings are published in the April 7th online edition of Science Translational Medicine, an American Association for the Advancement of Science publication.
All the blood circulating through the human body must be pumped out by the heart and flow though the aorta. These two vital organs must maintain structural integrity in the face of mechanical and biochemical stress, otherwise lethal consequences such as heart failure, aortic aneurysms, and aortic dissection can develop. While it has been known that diseases of the heart and aorta can co-exist, for example in Marfan's syndrome, pregnancy, aging, and growth hormone excess, the cardiovascular diseases are typically treated independently. The identification of shared molecular mechanism offers new promise for current and future treatment options.
"This is very rare to find a singular genetic factor that governs the response of the entire cardiovascular system. Our research proves KLF15 governs the shared diseases of the heart and blood vessels," says Mukesh K. Jain, M.D., F.A.H.A., senior author of the study and Director of the Case Cardiovascular Research Institute at Case Western Reserve University and the Chief Research Officer for the Harrington-McLaughlin Heart and Vascular Institute at University Hospitals Case Medical Center. In 2002, while at Brigham and Women's Hospital/Harvard Medical School, Dr. Jain and his team of researchers discovered KLF15.
Dr. Jain, along with his fellow researchers from the University of Pennsylvania, University of Medicine and Dentistry of New Jersey, Geisinger Health System, and Harvard Medical School, first observed reduced KLF15 levels in human patients with heart failure or aortic aneurysms. Subsequently, they bred genetically-modified mice deficient in only KLF15; this was where the link between diseases was identified. A major mechanism by which KLF15 exerts its protective effects is through the inhibition of a protein called p53. In some human body tissues, p53 can protect against cancer with its ability to shut down cell growth and new blood vessel formation. However, the researchers found that excess activation of p53 in both the heart and aorta is harmful, particularly when there is KLF15 deficiency. In fact, the mice showed dramatic improvement when the p53 gene was inactivated. The study also showed that KLF15 can block p53's harmful effects on the cardiovascular system by interfering with a process called protein acetylation. Lastly, the research team used the newly discovered molecular pathway to show that blocking the acetylation of p53 with a compound called curcumin can also protect against heart and aortic disease. Curcumin is the active compound in turmeric, a spice commonly used in Asian cuisine. They hope to harness the function of KLF15 as a drug target which might allow them to selectively block only the harmful effects of p53 in the cardiovascular system, while maintaining its anti-cancer effects in other organs.
Cardiovascular diseases are the leading cause of death and disability in developed countries. Despite the widespread use of medication, many people still suffer complications from these devastating diseases. "The discovery of new molecular pathways that are amenable to therapeutic manipulation is of immense clinical value. Our current study demonstrates proof-of-principle that KLF15 deficiency causes heart failure and aortic aneurysm formation. Thus, we believe that boosting the protective effects of KLF15 in the heart and aorta can prevent the initiation or progression of these diseases," say Saptarsi M. Haldar, M.D. and Yuan Lu, Ph.D., co-first authors on the paper. Dr. Haldar is an Assistant Professor of Medicine and Dr. Lu is a Research Associate in the Case Cardiovascular Research Institute at Case Western Reserve University School of Medicine.
As they look to the future, the researcher team will enhance KLF15's health-giving effects using a variety of approaches. They hope to discover compounds that can increase KLF15 levels or augment its function in the cardiovascular system, which includes screening a library of compounds for their ability to increase levels of the genetic factor. The research also has exciting implications for Marfan's syndrome, a multisystem disease involving the aorta and heart. The current work suggests that the KLF15-p53 axis might be a disease-modifying factor in the syndrome and serve as a potential therapeutic target.
"We hope that such therapies would help maintain the normal pumping-function of the heart and the integrity of aortic structure and thereby prevent patients from developing life-threatening complications such as sudden cardiac death, aortic rupture and aortic dissection," concludes Dr. Jain.
About Case Western Reserve University School of Medicine
Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Eleven Nobel Laureates have been affiliated with the school.
Annually, the School of Medicine trains more than 800 M.D. and M.D./Ph.D. students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News &World Report "Guide to Graduate Education."
The School of Medicine's primary affiliate is University Hospitals Case Medical Center and is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002.
Further reports about: > Genetic clues > KLF15 > Medical Wellness > Science TV > aortic aneurysms > blood vessel > cardiovascular disease > cardiovascular system > devastating disease > health services > heart failure > human body > molecular mechanism > molecular pathway > vascular disease > vascular system
Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University
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...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
17.01.2017 | Earth Sciences
17.01.2017 | Materials Sciences
17.01.2017 | Architecture and Construction