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CARDIAC FIBROBLAST PLAYS POTENTIALLY KEY ROLE IN RECOVERY AFTER HEART ATTACK, TEMPLE SCIENTISTS FIND

January 21, 2013

 

A type of heart cell called a fibroblast may play a surprisingly important role in how the heart recovers after a heart attack. Scientists at the Center for Translational Medicine at Temple University School of Medicine have found evidence in mice that when a specific protein, GSK-3α, is turned off in cardiac fibroblasts, the heart has a much easier path to recovery. The results suggest that fibroblasts – better known for their part in the development of myocardial fibrosis, a leading cause of heart failure – may instead now be seen as a potential target in preventing heart failure after a heart attack.

 

“These results establish for the first time the potential role of cardiac fibroblasts in recovery after a heart attack, and in turn, may lead to new research directions,” said Hind Lal, PhD, an Associate Scientist in the Department of Pharmacology and the Center for Translational Medicine at Temple University School of Medicine.

 

“The effects from deleting GSK-3α are very striking,” said senior author Thomas Force, MD, Professor of Medicine and Clinical Director of Temple’s Center for Translational Medicine. “If our goal is to maintain heart cell function after a heart attack, and to prevent remodeling and heart failure, then it appears that we need to pay more attention to the role of fibroblasts in the recovering heart.”

 

The team’s findings, reported in November at the American Heart Association’s Scientific Sessions 2012 in Los Angeles, are part of the Center’s larger efforts to better understand the nuances of the heart’s ability to recover after a heart attack, and ultimately, to find ways to head off the development of heart failure.

 

When cardiac fibroblasts, the most common type of cell in the heart, produce excess collagen protein, the result can be myocardial fibrosis, which is characterized by abnormal scarring in the heart. Such scarring affects the ability of the heart’s ventricles to pump blood, leading to heart failure. Fibroblasts have been thought to play a much lesser role in the processes that cause the heart to enlarge and reshape itself (remodeling) after a heart attack. Remodeling occurs as the damaged heart attempts to regain some of its lost function, but it is often harmful, and is another step on the road to heart failure.

 

Earlier research by Dr. Lal, Dr. Force and their co-workers showed that turning off the activity of GSK-3α in myocytes, another type of heart cell, in mice that have had a heart attack could prevent heart remodeling, preserve heart function and significantly improve survival. GSK-3α and its chemical cousin, GSK-3β, are important enzymes involved in various cellular processes and diseases, and studies indicate GSK-3α is important in regulating the heart’s growth, ability to contract, and its expansion in size associated with heart failure.

 

To find out the specific roles of GSK-3α and GSK-3β in cardiac fibroblast cells in remodeling and in the development of heart failure after a heart attack, the researchers created two mouse models: one in which mice lacked GSK-3α in all of the heart’s fibroblast cells, and another in which mice were missing the protein GSK-3β, again only in fibroblast cells. The researchers compared the effects of experiencing a heart attack among three groups of mice – animals lacking GSK-3α in fibroblast cells, those missing GSK-3β in fibroblast cells, and normal mice.

 

Only two weeks after the myocardial infarction, animals lacking GSK-3β showed a markedly reduced ability of the heart’s left ventricle’s to effectively pump blood compared to the other two groups. By six weeks, their hearts showed greater fibrosis and remodeling, and the mice experienced more heart failure. The mice also had a higher death rate after having a heart attack (57.1 percent) compared to control mice (29.4 percent).

 

In contrast, both the normal mice and the mice lacking the GSK-3α protein in heart fibroblast cells initially had similar swelling in the left ventricle and difficulties pumping blood after a heart attack. After four weeks, however, the effects on these two groups began to diverge. The mice without GSK-3α showed fewer changes in left ventricle size and function compared to the normal mice. At eight weeks, differences were even more pronounced, and the genetically normal mice continued to deteriorate much more than the mice lacking GSK-3α.

 

The findings suggest that turning off GSK-3α protein in heart fibroblast cells protects against heart remodeling and loss of function after a heart attack, said Dr. Lal. They also indicate that cardiac fibroblast GSK-3α and GSK-3β exhibit opposite effects on cardiac remodeling and heart function after a heart attack.

 

“The results establish the driving role of fibroblasts in heart attack-induced remodeling,” said Dr. Lal. “Surprisingly, we found that both forms of GSK have distinctly different roles in remodeling.” Earlier work in heart muscle cells showed that turning off GSK-3β was actually beneficial, in contrast to the current findings in fibroblasts.

 

Dr. Lal said the research team would like to better understand the various mechanisms behind these observed differences in behaviors between the two forms of GSK and the different heart cell types.

 

“Therapeutically, we’ll want to see how manipulating these protein signals can affect the heart,” Dr. Force added. “One way might be to target fibroblasts with small molecules.”

 

Other authors who contributed to the research include Firdos Ahmad, Ronald J. Vagnozzi, Jibin Zhou, Mahek Shah, and Erhe Gao, Temple University School of Medicine, and James Woodgett, University of Toronto.

 

This work was supported by grants HL 061688 and HL09199 from the National Heart Lung and Blood Institute, part of the National Institutes of Health.