Heart diseases contribute to a large number of deaths every year. Stroke and heart attacks are two of the major threats to public health in virtually every country. However, recent research by a team of scientists at the University of Texas Southwestern Medical Center reveals that the after-effects of these two traumatic events can actually be beneficial against further health threats.
The two events that have been linked in this study are the Unfolded Protein Response (UPR) and the formation of protein molecules with glucose molecules of different conformations attached to their ends. This study was led by Dr. Joseph A.Hill Professor of Internal Medicine and Molecular Biology, and senior author of the study, Dr. Zhao Wang, postdoctoral research fellow and first author of the paper, along with other researchers from UT Southwestern, including Dr. Yingfeng Deng, a postdoctoral research fellow at the Touchstone Center for Diabetes Research; Ningguo Gao, senior research scientist in pharmacology; Dan L. Li, graduate student research assistant in internal medicine; Cyndi Morales, graduate student research assistant in internal medicine; Dr. Alfredo Criollo, postdoctoral researcher in internal medicine; Dr. Xiang Luo, assistant professor of internal medicine; Wei Tan, research scientist in molecular biology; Nan Jiang, senior research scientist of internal medicine; Dr. Mark A. Lehrman, professor of pharmacology; Dr. Beverly A. Rothermel, associate professor of internal medicine and molecular biology; Dr. Pradeep P. A. Mammen, associate professor of internal medicine; Dr. Anwarul Ferdous, assistant professor of internal medicine; Dr. Thomas G. Gillette, assistant professor of internal medicine; and Dr. Philipp E. Scherer, professor of internal medicine and cell biology.
The study was published in the March 2014 issue of the online journal Cell and was funded by grants from the National Institutes of Health, the Cancer Prevention and Research Institute of Texas (CPRIT), the American Heart Association–DeHaan Foundation, the Fondation Leducq, and the American Diabetes Association.
About The Study
The basis of this study comes from the initiation of ischemia — a condition where the cardiac muscles are deprived of oxygen and nutrients — and a subsequent repercussion, which restores the original conditions either on its own or therapeutically. Ischemia in the heart is brought about as a result of heart attacks, strokes, or other underlying injuries to the liver, kidney, and lungs, among other organs. Laboratory studies (published in September 2009, J Mol Cell Cardio) have shown that ischemia mimics the conditions that induce stress in the heart, similar to that formed by a lack of oxygen and glucose. This stress leads to misfolding or incomplete folding of necessary proteins by the Endoplasmic Reticulum (ER). It is during this time that the UPR pathway comes into play.
The UPR pathway is a highly conserved signal transduction pathway, which occurs at times of ER stress and accumulation of unfolded proteins near the lumen of the cell. Now, during normal conditions, a class of proteins called the Glucose Response protein 78 (GRP 78) is bound to the luminal domains of the effector molecules of UPR. As stress is induced in the ER as a result of ischemia, the GRP 78 translocate to the ER to aid in protein folding, releasing these bound effector molecules. Inositol Required Enzyme-1 (IRE-1) is one such molecule which is released, and it induces transcription of ER stress regulator genes, which also helps the ER in protein folding. IRE-1 does so by splicing a protein called the X-Box Binding protein 1 (XBP-1).
The splicing of XBP-1 acts as a direct activator of a metabolic pathway called the Hexosamine Biosynthetic Pathway (HBP). Hexosamine is a cellular sensor of glucose activity in the body and is necessary for glycosylation of the sereine and threonine residues of the proteins. Glycosylation adds modified glucose molecules to the protein by O-GlcNAcylation. This in turn exerts a protective effect on the injured cells and prevents them from undergoing further trauma.
This chain of events was the key to this study, as earlier there was no conclusive evidence as to how modified glucose molecules were added to the proteins and what triggered the O-GlcNAcylation. As Dr. Hill put it: “We discovered a linear cascade downstream of ischemia/reperfusion that involves UPR activation, elicitation of Xbp1s, consequent activation of the HBP, and robust cardioprotection.It is the first time that researchers have been able to unveil a clear pathway leading to significant cardioprotection, often thought of as the ‘holy grail’ of cardiology.”
Though it still remains to be seen as to how the O-GlcNAcylation exerts a protective effect on the heart, there is now a possibility that further research into this topic can lead to therapeutic options for treating heart diseases. As Dr. Hill pointed out, “If we can find a way to enhance Xbp1s in the heart, it could be a very significant medical advancement.At this juncture, however, we’re extremely pleased to have uncovered a major pathway that leads to protecting the heart in the face of danger.”