Novel DNA Repair-Independent Roles of DNA-PKcs in Hypercholesterolemia-Induced Atherosclerosis
Abstract
A high level of cholesterol in the blood stream predisposes individuals to severe cardiovascular diseases. The World Health Organization reported that 17.9 million people die every year due to cardiovascular diseases. Several risk factors have been identified for the development of such pathological conditions: physical inactivity, excessive use of tobacco and alcohol, and unhealthy diet. Despite a heathy lifestyle and the substantial improvement in the treatment of hypercholesterolemia, essentially due to the introduction of statins in the standard therapy, many patients still fail to lower the levels of lipids recommended by guidelines, resulting in a loss of clinical benefits. Defining the molecular and cellular processes underlying the complexity of the disease is essential. One of the major consequences of high levels of cholesterol in the blood is the formation of plaques on the surface of the arteries, making them very narrow. This condition is called atherosclerosis. Atherosclerosis is a silent disease that can stay without symptoms for years. Most of the time, patient realize that they have the disease only when they experience some consequent major event such as stroke or heart attack. We identified a new potential target for the treatment of such condition. We demonstrated that a protein, primarily known for its role on DNA repair (DNA-PKcs), could also play a major role in cardiovascular inflammation and the development of atherosclerosis. Initially, naively, we speculated that the relevant function of this protein was strictly linked to DNA damage. However, with more knowledge, it became evident that the role of this enzyme might be independent of its traditional role in DNA repair. This is due to two issues: (1) the enzyme is highly abundant in cells and (2) the DNA repair process requires minute levels of the enzymes (e.g., less than 1% of DNA-PK). Our laboratory previously found that genetic inhibition of DNA-PKcs is sufficient to block asthma, another inflammatory disease. Such effects correlated with a marked reduction in production of several specific inflammatory molecules. We hypothesize that the role of DNA-PKcs may be a master regulator of inflammation during the development of atherosclerotic plaques. The role of DNA-PKcs in such inflammation does not require the assistance of other factors that are requisite for DNA repair. We propose DNA-PKcs to be considered as a unique enzyme that is completely distinct from its trimer DNA-PK responsible for DNA repair processes. We will use sophisticated approaches that include an animal model of hypercholesterolemia-induced atherosclerosis and a platform of cell culture system to unravel the mechanism by which DNA-PKcs functions during inflammation. We plan also to test Nedisertib, a drug already approved for clinical trial, in our animal model. We are confident that the completion of the proposed studies will allow us to establish a completely novel and unprecedented DNA-repair independent function for DNA-PKcs in atherosclerosis and determine the mechanism(s) by which this new enzyme plays a critical role in inflammation of arteries. This proposal puts forth a very novel and paradigm-shifting concept that challenges the current understanding on the role of DNA-PKcs in cellular and tissue processes. Unraveling the mechanism by which the kinase function provides a platform on which new drugs can be developed in such a way that DNA repair processes are not interfered with. Even if our proposed study is highly relevant for the improvement of the health of military uniformed Service Members currently serving or Veterans, because of their higher risk to develop cardiovascular disease, we would like to emphasize that the general public could also benefit from our research. More importantly, the benefit of our study can also be extended to other inflammatory diseases.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310229
Entities
People
- Hamid Boulares
Organizations
- LSU Health Sciences Center New Orleans
- United States Army