Scientists discover novel protein partnership that provides vascular protection
Researchers at UT Southwestern Medical Center have identified a novel protein partnership that promotes vascular healing and may protect against a number of blood vessel disorders including atherosclerosis.
The study, published online July 8 in the Journal of Clinical Investigation, reveals new mechanisms that may be harnessed in the future to obtain the benefits of activating receptors known as Liver X Receptors (LXRs) while avoiding adverse actions of LXRs that have thwarted therapeutic progress to date.
“LXRs, which were originally discovered by Dr. David Mangelsdorf, our Chair of Pharmacology here at UT Southwestern, classically function in the cell nucleus to govern genes involved in cholesterol regulation. Initially, there was great hope that LXRs could be modulated to prevent or treat cholesterol-related diseases such as atherosclerosis. However, it was found that global activation of LXRs has both beneficial and detrimental consequences, ” said Philip Shaul, M.D., Professor of Pediatrics at UT Southwestern. Dr. Shaul and Michihisa Umetani, Ph.D., Assistant Professor of Pediatrics and Pharmacology, are senior authors of the report.
The study examines how LXRs function in vascular endothelial cells, which comprise the single layer of cells that line the inside of all blood vessels.
It is known that LXRs are important in maintaining proper cholesterol levels in the circulation, and this is mediated primarily by an isoform of the receptor designated LXRalpha, which is abundant in the liver, Dr. Umetani said. Work in animal models has demonstrated that the activation of LXRs provides protection from atherosclerosis.
However, therapies targeting LXRs have been disappointing because their activation causes excess lipid production in the liver through processes involving LXRalpha. The problem is that agents targeting LXRs activate both the alpha isoform and the second isoform known as LXRbeta, Dr. Umetani said.
“We found that in the endothelium LXRbeta is highly functional whereas LXRalpha is of minimal consequence, and that in the endothelium LXRbeta robustly promotes blood vessel repair and the synthesis of the atheroprotective signaling molecule nitric oxide,” Dr. Umetani said.
While studying the mechanism of action of LXRbeta in endothelium, the research team made two surprising discoveries. First, they found that the primary actions of LXRbeta occur outside of the nucleus and involve a population of receptors located in specialized compartments on the cell membrane known as caveolae/lipid rafts. Second, they discovered that the capacity of LXRbeta to initiate signaling events within endothelial cells requires partnership with the receptor for estrogen.
“We previously determined that the potential for estrogen to afford cardiovascular protection involves estrogen receptor function outside of the nucleus, whereas the hormone’s ability to promote cancer entails receptor function within the nucleus,” Dr. Umetani said. “So, LXRbeta partners with the favorable functions of estrogen receptors to provide protection of the blood vessel wall.”
“Evidently, as in real estate, the key to success in providing vascular protection may be location, location, location,” Dr. Shaul said.
The research holds promise for new treatments.
“If we can selectively target LXRbeta, or specifically leverage the LXR-estrogen receptor partnership in endothelial cells, we may be able to protect vascular health and get all of the benefits without the negatives such as fatty liver and the inflammation and scarring and possible liver failure that can ensue,” Dr. Umetani said.
Tomonori Ishikawa, Ph.D, postdoctoral researcher, and Ivan Yuhanna, Ph.D., equally shared first lead authorship of the study. Junko Umetani, research assistant; and Dr. Wan-Ru Lee, Ph.D., research associate, also contributed to the study.
Read about the research that Dr. Shaul and Dr. Umetani are conducting into vascular disease at their lab website.