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Study links inflammation and calcium signaling in heart attack

Research reveals new role for immune system pathway in post-heart attack inflammation

A new study led by University of Iowa researchers has found an unexpected new link between this inflammation in heart muscle following a heart attack and a previously known enzyme called calcium/calmodulin-dependent protein kinase II or CaM kinase II. The findings also reveal the involvement of an immune system gene -- complement factor B -- that has been implicated in other inflammatory diseases.

The study, published online March 9 in the Journal of Clinical Investigation, suggests that CaM kinase II inhibition could be a therapeutic target in heart disease, but by previously unknown pathways.

CaM kinase II is a pivotal enzyme that registers changes in calcium levels and oxidative stress and translates these signals into cellular effects, including changes in heart rate, cell proliferation and cell death. CaM kinase II also regulates gene expression -- which genes are turned on or off at any given time. Inhibition of CaM kinase II in mice protects the animals' hearts against some of the damaging effects of a heart attack.

To better understand how CaM kinase II pathways are involved in damage caused by heart attack, the UI researchers investigated the effect of CaM kinase II activity on gene expression during a heart attack. The study's lead author was Madhu Singh, Ph.D., UI research scientist, and the senior author was Mark Anderson, M.D., Ph.D., professor of internal medicine and molecular physiology and biophysics at the UI Roy J. and Lucille A. Carver College of Medicine and director of the Division of Cardiovascular Medicine.

"We used a mouse model in which CaM kinase II is inhibited in heart muscle cells. These mice are protected from many of the ill effects of heart attack," Singh said. "We compared a large number of genes that were expressed in the protected mice compared to the non-protected control mice. A particularly interesting finding was that a cluster of inflammatory genes was differently expressed depending on whether CaM kinase II was active or inhibited."

Specifically, the research showed that heart attack triggered increased expression of a set of pro-inflammatory genes, and inhibition of CaM kinase II substantially reduced this effect.

The team focused on the most highly regulated of these inflammatory genes -- complement factor B. The protein produced by this gene is involved in the innate immune system called the alternative complement pathway.

The team found that complement factor B protein is synthesized in heart muscle cells as part of an autoimmune response to heart attack and that complement factor B protein participates in the formation of the so-called membrane attack complex, which punctures holes in heart cell membranes.

"It was very surprising that heart muscle cells express complement factor B, an immune system protein, because traditionally these cells are known for their contraction function, which supports heart pumping, not as part of the immune response to injury," Singh said.

Complement factors are part of the first line of defense against pathogens. When complement pathways are triggered, a biological cascade is set in motion that results in the formation of a membrane attack complex – a group of proteins that can literally punch holes in the cell membrane of an invading microbe or an injured cell.

The UI team showed that the complement factor B produced in heart muscle cells helped form membrane attack complexes that were able to puncture the cell membranes of heart muscle cells in a petri dish. In addition, the researchers found that genetically engineered mice that did not express functional complement factor B were partly protected from heart attack -- showing reduced mortality and heart damage.

"Clearly, if this immune system response is induced during heart attack injury, it might amplify heart damage by poking holes in the cell membrane," Singh said. "Not only is the heart trying to recover from the injury induced by the heart attack, but it also has to deal with the consequences of the induced activity of the complement pathway, which is attacking the cell membranes.

"If we can reduce the extra burden on the heart by some means of inhibiting this activity, then clinically that might be useful, he added.

"These findings show a previously unanticipated connection between CaM kinase II activity and inflammation in heart muscle and show that this connection drives maladaptive responses to heart attack," said Anderson, who also holds the Potter-Lambert Chair in Cardiology. "By understanding these CaM kinase II signaling mechanisms that occur inside the cell we might arrive at new and better drug targets that act more specifically to treat a variety of heart problems."

Jennifer Brown | EurekAlert!
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