The Akt kinase has long been known as a molecule that protects the heart after damage. But in the December 2007 issue of Nature Medicine, researchers report that Akt partially may be taking the credit for work done by another kinase: Pim-1.
The effects of Akt "need to be interpreted and rethought in light of Pim-1 contributions," senior author Mark Sussman, a member of the San Diego State University Heart Institute, told BioWorld Today.
Akt is known to interact with Pim-1 in blood stem cells, but previously had not been studied in the heart. Sussman and his team first studied the amounts of Pim-1 in the hearts of newborn, juvenile and adult mice, and found that it decreased as the animals grew up, suggesting that it could play a role in cell proliferation during cardiac development. In both human heart tissue samples from patients with heart failure and mice with experimentally induced heart failure, Pim-1 was up-regulated.
The scientists next tested the roles of Akt and Pim-1 and their relationship in protecting heart muscle cells in response to injury. In cultured cells, heart muscle cells showed less cell death in response to pro-apoptotic stimuli if they overexpressed Pim-1, whereas cells expressing nonfunctional Pim-1 showed increased cell death.
Several cardioprotective agents induced Pim-1 expression, and that induction could be prevented by mutant Akt, leading the researchers to conclude that Akt is activating Pim-1. However, for Akt to be effective, it had to be overexpressed in the nucleus; overexpressing Akt throughout the cell was "not particularly effective" at inducing Pim-1, Sussman said
Pim-1 knockouts have more damage in response to induced myocardial infarct, whereas mice overexpressing Pim-1 specifically in the heart were protected somewhat against the effects of an induced infarct.
On a practical level, those results mean that targeting Pim-1 potentially could induce heart cells to divide and replace cells that are damaged during a heart attack or heart failure. Sussman said that his lab currently is testing whether stem cells engineered to overexpress Pim-1 would be able to help repair damaged hearts.
Earlier studies have shown that stem cell transplants improve cardiac function, but Sussman noted that those improvements are "marginal, and probably not due to the cells themselves, which mostly disappear." In contrast, he said, his lab has seen "impressive" effects of Pim-1-engineered stem cells on heart function in animal studies.
Pim-1, like Akt itself, is known best as an oncogenic kinase. When asked whether that might present problems in clinical development, Sussman replied that while the kinases are "obviously important in cancer," there are significant differences between tumor cells and normal heart muscle cells.
Tumor cells are dividing rapidly and are resistant to cell death, and in that context, an overexpressed or hyperactive kinase is more or less the last thing a cell needs.
In contrast, Sussman said, cardiac cells are very reluctant to divide, even in response to proliferative stimuli. Usually, he said, "they just get big," growing but not dividing.
Tumor cells also usually have multiple abnormalities by the time they start dividing uncontrollably, and Sussman said that his team's work so far suggests that revving up Pim-1 in a cardiac stem cell does not turn it onto a cancer cell.
"We see no evidence of tumorigenicity to date."