Research findings link post-heart attack biological events that provide cardioprotection

March 13, 2014
This image shows Dr. Joseph A. Hill, (left) Chief of Cardiology and senior author of the study, and Dr. Zhao Wang, a postdoctoral research fellow and the study's first author. Credit: UT Southwestern Medical Center

Heart attack and stroke are among the most serious threats to health. But novel research at UT Southwestern Medical Center has linked two major biological processes that occur at the onset of these traumatic events and, ultimately, can lead to protection for the heart.

On one end of the cascade is the so-called Unfolded Protein Response (UPR), and at the other end are numerous proteins with modified glucose molecules attached to them. For years, researchers have made countless observations relating to these opposite ends of the spectrum. Now, researchers at UT Southwestern have discovered a pathway that links these two disparate biological occurrences, which could open the door for new types of treatment.

"Our findings uncover the direct coupling of these two important pathways and raise the prospect of therapeutic manipulation of the UPR to lessen the damage caused by heart attack and stroke," said Dr. Joseph A. Hill, Professor of Internal Medicine and Molecular Biology, and senior author of the study published in the March 13 issue of Cell.

The work by Dr. Hill's team uncovers a previously unrecognized progression following ischemia (when a tissue is deprived of oxygen and nutrients) and reperfusion (when that supply is restored, either spontaneously or therapeutically). Ischemia/reperfusion injury underlies health issues such as heart attack, stroke, and numerous other ailments including diseases of the kidney, liver, skeletal muscles, and more.

When someone suffers a heart attack, it triggers the process of the UPR inside myocytes (heart cells). A link between ischemia/reperfusion and UPR has been suggested previously, but compelling evidence was absent until the Cell study emerged.

Of the three pathways activated within the UPR, the new work implicates IRE1, which produces a molecule called spliced X-box binding protein 1 (Xbp1s), as a direct activator of the hexosamine biosynthetic pathway (HBP). The HBP is responsible for producing modified glucose molecules that couple to numerous proteins, leading to beneficial changes in their function, stability, and location within the cell. This coupling, termed O-GlcNAcylation, has favorable effects on disease-injured cells, including myocytes.

Previously, researchers have verified that the O-GlcNAcylation process provides ample protection for the heart, in addition to many other cell types and tissues. However, what activated the O-GlcNAcylation process was unknown, until now.

"We discovered a linear cascade downstream of ischemia/reperfusion that involves UPR activation, elicitation of Xbp1s, consequent activation of the HBP, and robust cardioprotection," said Dr. Hill, also the Chief of the Division of Cardiology and Director of the Harry S. Moss Heart Center. "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."

While it is clear that the O-GlcNAcylation process protects the heart, we still do not understand how protection is mediated, notes Dr. Hill.

"However, now we know what turns the process on, a finding that points the way to future research and possibly new therapeutic means by which to safeguard the heart," he said.

The study, undertaken by Dr. Zhao Wang, postdoctoral research fellow and first author of the paper, directly raises the question of whether Xbp1s can be manipulated therapeutically. If the body is able to produce more Xbp1s, then doing so would enhance the heart's ability to withstand a . In fact, using mice engineered to have extra copies of Xbp1s in the heart, Dr. Wang initiated heart attacks that were ultimately smaller and less harmful to the host. Conversely, when he deleted the gene altogether and initiated heart attacks, the effects were much larger and more harmful to the carrier.

"If we can find a way to enhance Xbp1s in the heart, it could be a very significant medical advancement," Dr. Hill said. "At this juncture, however, we're extremely pleased to have uncovered a major pathway that leads to protecting the in the face of danger."

Explore further: Unfolded protein response contributes to sudden death in heart failure

Related Stories

Unfolded protein response contributes to sudden death in heart failure

December 2, 2013
A researcher at the Cardiovascular Institute (CVI) at Rhode Island, The Miriam and Newport hospitals has found a link to human heart failure that if blocked, may reduce the risk of sudden cardiac death. The paper, written ...

The X factor in liver metabolism

December 21, 2012
After you eat, your liver switches from producing glucose to storing it. At the same time, a cellular signaling pathway known as the unfolded protein response (UPR) is transiently activated, but it is not clear how this pathway ...

Cardiologists identify mechanism that makes heart disease worse in diabetics

March 1, 2012
UT Southwestern Medical Center cardiologists have uncovered how a specific protein's previously unsuspected role contributes to the deterioration of heart muscle in patients with diabetes. Investigators in the mouse study ...

Drug can reverse overgrown hearts to help prevent heart failure

May 31, 2011
A promising cancer treatment drug can restore function of a heart en route to failure from high blood pressure, researchers at UT Southwestern Medical Center have found.

Compound developed by scientists protects heart cells during and after attack

February 7, 2013
Using two different compounds they developed, scientists from the Florida campus of The Scripps Research Institute (TSRI) have been able to show in animal models that inhibiting a specific enzyme protects heart cells and ...

Misplaced protein causes heart failure

March 6, 2014
Colchicine, a drug that's used to treat gout, has the beneficial side effect of lowering the risk of heart attack in patients taking it. Conversely, taxol, a drug for treating cancer, has the opposite effect; raising the ...

Recommended for you

Inhibiting a protein found to reduce progression of Alzheimer's and ALS in mice

August 17, 2017
(Medical Xpress)—A team of researchers with Genetech Inc. and universities in Hamburg and San Francisco has found that inhibiting the creation of a protein leads to a reduction in the progression of Alzheimer's disease ...

Are stem cells the link between bacteria and cancer?

August 17, 2017
Gastric carcinoma is one of the most common causes of cancer-related deaths, primarily because most patients present at an advanced stage of the disease. The main cause of this cancer is the bacterium Helicobacter pylori, ...

Using barcodes to trace cell development

August 16, 2017
How do the multiple different cell types in the blood develop? Scientists have been pursuing this question for a long time. According to the classical model, different developmental lines branch out like in a tree. The tree ...

The unexpected role of a well-known gene in creating blood

August 16, 2017
One of the first organ systems to form and function in the embryo is the cardiovascular system: in fact, this developmental process starts so early that scientists still have many unresolved questions on the origin of the ...

Researchers unlock clues to how cells move through the body

August 16, 2017
During its 120-day cycle the circulatory system transports red blood cells and nutrients throughout the human body. This system helps keep the body in balance and fight against infections and diseases by filtering old or ...

Eating habits affect skin's protection against sun

August 15, 2017
Sunbathers may want to avoid midnight snacks before catching some rays.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.