February 2010

Heart Matters

Daria Mochly-Rosen 

Professor of chemical and systems biology, Stanford School of Medicine

Daria Mochly-Rosen was introduced to protein kinase C through her postdoctoral mentor, Daniel Koshland, and has since been instrumental in uncovering this enzyme’s role in heart function.

In an unusual twist, a run-of-the-mill lecture at a conference became the catalyst for Daria Mochly-Rosen’s foray into an exciting new line of research.

In the mid-1990s, Mochly-Rosen showed that different isozymes of protein kinase C were located in discrete subcellular regions of cardiac muscle cells and that shutting off individual isozymes with peptides could make the cells beat faster or slower. This finding confirmed her hypothesis that PKC isozymes have unique localizations in all cells, mediated by binding to isozyme-specific anchoring proteins known as receptors for activated C-kinase, or RACKs.

The identification of RACKs helped explain the mystery of how the many similar-appearing forms of PKC could mediate a range of processes in diverse— and, in the case of heart muscle, even opposite— ways.

“However, when I presented these results at an American Heart Association conference, I noticed a lot of uninterested scientists in the audience,” she says. Afterwards her colleague Joel Karliner of the University of California, San Francisco, informed her that cardiologists didn’t really care about heart rate, because they had perfectly good ways of managing it.

“So I asked him what cardiologists did care about, and he told me heart attacks,” Mochly-Rosen says. However, she was hardly familiar with this area. (A biochemist by training, she had primarily worked with heart cells because their beating was an easy phenotype to observe.) “But then Joel told me not to worry— he would ask one of his cardiology fellows, Mary Gray, to join my lab.”

Since then, Mochly-Rosen always has had at least one physician in her lab at Stanford University to help with her research into PKCs role in heart function, and her group has uncovered a lot of valuable information, including the fact that either activation of epsilon PKC or inhibition of delta PKC can protect the heart from ischemia damage. In fact, one of the delta PKC inhibitor peptides she used in her earlier heart rate studies (delta V1-1) is now in phase II clinical trials for heart attack treatment.

“The people at the AHA conferences are a bit more attentive when I speak now,” she jokes.

In the past couple of years, Mochly-Rosen has turned her attention to one of the proteins activated by PKC; through a proteomic approach aimed at understanding how epsilon PKC is heart-protective, she identified aldehyde dehydrogenase 2 as an epsilon PKC target. She then confirmed a causal relationship between epsilon PKC and ALDH2 (alcohol dehydrogenase) by developing a small molecule activator of ALDH2 and showing that this activator produced the same cardioprotective effects in rat models as epsilon PKC activation.

Mochly-Rosen and her lab are now looking at exactly why PKC turns on ALDH2 to protect the heart. However, the importance of ALDH may be the key to the complex role of alcohol in relation to the heart, as alcohol consumption has been linked to both beneficial and damaging cardiac effects.

At the least, this new revelation gives Mochly-Rosen her own change in perspective. “I always thought ALDH was a boring enzyme; it was always active and seemed to have a simple function,” she says. “But now I know better.”

Journal of Biological Chemistry research highlight: RBCK1, a Protein Kinase CβI (PKCβI)-interacting Protein, Regulates PKCβ-dependent Function. JBC 282, 1650-1657.

More Heart Matters with Mark A. Sussman. 

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