February 2010

Heart Matters

Mark A. Sussman

Professor of biology, San Diego State University

Science-Focus---Sussman
In 2006, Mark A. Sussman helped facilitate a National Institutes of Health program project grant for San Diego State University and the University of California, San Diego. It was the first such award for any school in the 23-campus California State University system.

When Mark A. Sussman completed his doctoral studies at the University of Southern California, he asked one of his thesis committee members on what area of science his postdoctoral fellowship should focus. “He told me to do something completely different than my graduate school research, because my postdoc was my last opportunity to be stupid, scientifically speaking.”

So, Sussman put his dissertation on viral immunology on the bookshelf and pursued his interests in the cytoskeleton, first with Velia Fowler at The Scripps Research Institute and then with Laurence Kedes back at USC. He began working on the actin-capping protein tropomodulin and found that the structural protein was expressed in specific subcellular locations in heart muscle, and, when it was over-expressed, it would prevent proper heart contraction and eventually led to heart failure as the organ tried unsuccessfully to remodel.

In the ricocheting world of science, that discovery soon led to a cardiovascular research fellowship, which, in turn, led to Sussman’s development of the first mouse model of dilated cardiomyopathy and a long and fruitful career studying heart failure.

However, when the California native returned home to take up a position at San Diego State University, he decided a change of pace was in order. “I had sort of become an expert in making mouse hearts that failed, and I now wanted to see what I could do to keep a heart working properly,” he says.

Sussman became intrigued with Akt/PKB kinase, a signaling protein that either helped protect heart cells or caused it to fail, depending who you asked. “It was a big paradox,” he says. “Researchers found that if you activated Akt in heart cells, by adding agents like insulin like growth factor to the media, it made the cells resistant to death. But, when they induced Akt in mice by genetic manipulation, the heart responded by remodeling and eventually failed.”

The reason for the paradox, as Sussman discovered, was that Akt goes through a specific set of localizations when activated and has specific targets, depending on where it is; in the case of cardioprotective stimulators, Akt ended up in the nucleus.

“So it’s not just activity level but where the activity occurs,” he says. “Thus, the brute-force approach of simply inducing Akt in the heart was like drinking water from a fire hose: You’ll quench your thirst, but a lot of bad stuff is going to happen as well.” Once Sussman mimicked the process seen in cell culture and localized Akt to the nucleus, the mice exhibited the expected damage-resistant hearts.

Those studies did present one mystery, though. Many of the important cardioprotective targets where in the cytoplasm; so how did Akt turn them on while trapped in the nucleus? The answer was that Akt turned on another activator protein called PIM-1, which mediates the protective effects.

And PIM-1, Sussman believes, is a key piece for regenerative medicine and stem-cell therapies for the heart. Early work in repairing hearts with stem cells was unsuccessful, because the stem cells did not graft well and died off; but combining stem cells with activation of PIM-1 and the survival pathway might make it work. Just recently, he had success in mouse models, and now he’s hoping for similar results using human cells in immunized mice and then large-animal models.

And if all goes as planned, Sussman thinks we might soon see a future of genetically rebuilding hearts after acute stress or chronic injury. “We’ll put the surgeons out of business, and I can spend my days on the beach, drinking cocktails with little umbrellas in them.”

Journal of Biological Chemistry research highlight: Coordination of Growth and Endoplasmic Reticulum Stress Signaling by Regulator of Calcineurin 1 (RCAN1), a Novel ATF6-inducible Gene. JBC 283, 14012-14021.

Nick Zagorski (nzagorski@asbmb.org) is a science writer at ASBMB.


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