Increased inflammation following a heart attack has been associated with worse outcomes for the patient.
A new study led by University of Iowa researchers has found an unexpected new link between the 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.
Investigate Effect
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, PhD, UI research scientist in internal medicine, and the senior author was Mark Anderson, M.D., PhD, 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.
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—and 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 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.
Membrane Attack
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.
"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." |
