JUPITER, FL, 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 surrounding tissue against serious damage from heart attacks. The compounds also protect against additional injury from restored blood flow after an attack, a process known as reperfusion.
The study, which was led by Philip LoGrasso, a professor and senior scientific director of discovery biology at Scripps Florida, appears in the February 8, 2013 print edition of The Journal of Biological Chemistry.
A heart attack severely restricts blood supply, starving heart cells and surrounding tissue of oxygen, which can cause enormous damage in relatively little time—sometimes in just a few minutes. Known as an ischemic cascade, this drop-off of oxygen results in a sudden crush of metabolic waste that damages cell membranes as well as the mitochondria, a part of the cell that generates chemical energy and is involved in cell growth and death.
Unfortunately, restoring blood flow adds significantly to the damage, a serious medical issue when it comes to treating major ischemic events such as heart attack and stroke. Reperfusion re-invigorates production of free radicals and reactive oxygen species that attack and damage cells, exacerbating inflammation, turning loose white blood cells to attack otherwise salvageable cells and maybe even inducing potentially fatal cardiac arrhythmias.
The new study found that inhibiting the enzyme, c-jun-N-terminal kinase (JNK), pronounced "junk," protected against ischemic/reperfusion injury in rats, reducing the total volume of tissue death by as much as 34 percent. It also significantly reduced levels of reactive oxygen species and mitochondrial dysfunction.
In earlier studies, TSRI scientists found that JNK migrates to the mitochondria upon oxidative stress. That migration, coupled with JNK activation, they found, is associated with a number of serious health issues, including liver damage, neuronal cell death, stroke and heart attack. The peptide and small molecule inhibitor (SR3306) developed by LoGrasso and his colleagues blocks those harmful effects, thereby reducing programmed cell death four-fold.
“This is the same story,” said LoGrasso. “These just happen to be heart cells, but we know that oxidative stress kills cells, and JNK inhibition protects against this stress. Blocking the translocation of JNK to the mitochondria is essential for stopping this killing cascade and may be an effective treatment for damage done to heart cells during an ischemic/reperfusion event.”
In addition, LoGrasso said, biomarkers that rise during a heart attack shrink in the presence of JNK inhibition, a clear indication that blocking JNK reduces the severity of the infarction.
The first author of the study, “Inhibition of JNK Mitochondrial Localization and Signaling is Protective Against Ischemia-Reperfusion Injury in Rats,” is Jeremy W. Chambers of TSRI. Other authors include Alok Pachori, Shannon Howard and Sarah Iqbal, also of TSRI. For more information, see http://www.jbc.org/content/early/2012/12/20/jbc.M112.406777.full.pdf
This work was supported by the National Institutes of Health (grant number NS057153) and by the Saul and Theresa Esman Foundation.
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
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