Calcineurin and Cardiac Disease

For this article, Eugene Russo interviewed Eric N. Olson, chair of molecular biology at the University of Texas Southwestern Medical Center, Dallas. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. J.D. Molkentin, J.R. Lu, C.L. Antos, B. Markham, J. Richardson, J. Robbins, S.R. Grant, E.N. Olson, "A calcineurin-dependent transcriptional pathway for cardiac hypertrophy," Cell, 93: 215-28, April 17, 1998. (Cited in more than 180 papers since publication) When Eric N. Olson and his colleagues stumbled upon a novel pathway that leads to cardiac hypertrophy--an enlargement of the heart triggered by most forms of cardiac disease--they raised more than a little controversy. It so happens that the pathway they discovered is governed by the calcium-dependent phosphatase calcineurin, the very same phosphatase that has routinely been the target of the immunosuppressive drugs cyclosporin A (CsA) and FK-506. By inhibiting calcineurin activity in T cells, CsA and FK 506 block an immune response and prevent tissue rejection. "The finding that calcineurin was regulating hypertrophy [suggested] that it might be possible to block hypertrophy at least in some situations by treatment with drugs already approved for use in people," comments Olson. The findings, he says, "electrified the field." Investigators latched on to the idea that calcineurin could be a mechanism for cardiac hypertrophy--which, when sustained, can lead to heart failure--and began trying to rescue all sorts of rodent models from hypertrophy using cyclosporin. Olson points out, though, that there are other, perhaps more treatment-ready, critical pathways. "Treating people with cyclosporin is not going to be the magic bullet for hypertrophy and heart failure," he emphasizes. Eric N. Olson Olson's lab embarked on this path to a "paradigm shift" rather innocently. His group generally focuses on cardiac development and had been studying many of the transcription factors involved in building the heart and the embryo, including a zinc finger protein called GATA4. They knew a lot about GATA4's role in embryogenesis, but less about its role in the adult heart's response to hypertrophy. When the adult heart hypertrophies, it attempts to revert to a fetal state by switching on a program of fetal cardiac genes, many of which are controlled by GATA4. Based on a hard look at the hypertrophy literature of the time, Olson's group suspected that the proximal upstream signal for inducing hypertrophy was a calcium signal: They hypothesized that something perturbed that signal, and then something happened--a "big black box," says Olson--that resulted in GATA4's sensing the calcium signal and activating the fetal gene program. Using embryo and cardiac libraries, Olson's team searched for GATA4 cofactors that might link it to a calcium or hypertrophic signaling system. They came up with the transcription factor NF-AT3. "It was like a light bulb went off in our head," recalls Olson. NF-AT3 had been studied extensively in T cells, where it was known to be a target for calcium signaling and stress responsiveness. But no one had suggested that NF-AT3 might be involved in the heart. NF-AT3 had, though, been shown to be involved in the immune response. When you stress a T cell, you activate calcium, which switches on calcineurin in the cytoplasm, which in turn dephosphorylates NF-AT3. NF-AT3 then enters the nucleus and turns on the necessary genes. Olson's group wondered if calcineurin might act upstream of NF-AT3 in the heart as well. They confirmed their hypothesis by showing that activating calcineurin in the heart could induce hypertrophy, and by showing that NF-AT3 itself could also induce hypertrophy directly. "This led to a really interesting model for how you could transmit a signal all the way from a membrane to the nucleus to activate hypertrophy," remarks Olson. There are likely to be complexities, however. Olson and his team are now looking to see where this apparently linear pathway might bifurcate, and at what steps in the pathway there might be built-in redundancies. They're also looking for related parallel pathways. Olson remains optimistic that these basic research findings will translate into an effective clinical treatment without major side effects such as immunosuppression. "The really important next step would be to try to direct an inhibitor of this pathway selectively to the heart," he comments. "If you could find a cardiac-specific inhibitor of the pathway and bypass the immune system, you might really have a magic bullet." Eugene Russo can be contacted at erusso@the-scientist.com

Calcineurin and Cardiac Disease

Interested in reading more?

Become a Member of