Science Editor

When developmental programs of the cell are re-started in adulthood, the resulting problem is often cancer: rapid division, growth and cell populations on the move characterize embryos as well as tumors.

In the July 1, 2010 issue of Nature, though, scientists reported on another problem that resulted from re-enactment of a developmental program. The cardiac enzyme Brg1, which is important during development, leads to cardiac hypertrophy when it is expressed in adults – which it is in response to stress.

Cardiac hypertrophy, along with heart muscle fibrosis or scarring, can lead to heart failure. It begins as a response to stressors such as high blood pressure, aortic valve malfunction or cocaine abuse. Senior author Ching-Pin Chang, assistant professor of cardiovascular medicine at Stanford University, and his colleagues found that that the enzyme Brg1 can lead to hypertrophy in adult hearts because of its influence on another protein: myosin.

Myosin heavy chains are the molecular motor of muscle cells, that is, they hydrolyze ATP, the energy currency of the cell, and contract to drive heartbeat.

Myosin heavy chains exit in two forms, alpha-MHC and beta-MHC. Over an animal's life span, Chang explained, the primary myosin form switches from beta to alpha.

"In mice, the fetal hearts do not pump as fast or as forcefully as the adult hearts to meet the circulatory need of the embryos," he told BioWorld Today. "Therefore, embryonic hearts use predominantly beta-MHC. Adult mouse hearts, on the other hand, beat at 500-600 times per minute and contract more forcefully . . . and therefore use primarily alpha-MHC."

Brg1 interacts with two other proteins, histone deacetylase, or HDAC, and poly-ADP ribose polymerase, or PARP, to influence gene expression via its effects on chromatin. The net result is repression of alpha-MHC and activation of beta-MHC.

When Brg1 is not present, as is usually the case in the adult heart, alpha-MHC is the predominant form of myosin. But Brg1 expression can be reactivated by cardiac stressors, and when it is, the predominant form of myosin will be beta-MHC, "a slower enzyme that fails to meet the physiological needs of the adult heart."

When Chang and his team prevented Brg1 expression in response to cardiac stressors, by conditionally knocking out the protein, hypertrophy decreased dramatically. "When the Brg1 gene is deleted, the stressed adult mouse heart has only minimal pathological changes," Chang said. "It does not have significant hypertrophy. There's no fibrosis or scarring."

Therapeutically, the findings mean that inhibiting Brg1 could be a useful weapon in the fight against cardiac hypertrophy. Targeting Brg1 directly, as opposed to HDAC and PARP, could have two advantages, Chang said.

"The formation of Brg1/HDAC/PARP complex . . . depends on the activation of Brg1 by cardiac stress. Therefore, targeting Brg1 may be equivalent to knocking down the activity of all these three important factors . . . that promote cardiac hypertrophy," Chang said. Targeting Brg1 might even have a synergistic effect with HDAC and PARP inhibitors.

The other advantage is that in adults, Brg1 appears to be a disease-specific protein. "Brg1 activity is very low in normal heart muscle cells, but its activity goes up in the hypertrophic hearts," Chang explained.

"A drug that targets and reduces Brg1 activity theoretically would not have high cardiac toxicity for normal heart muscle cells. This may be important because a drug that inhibits Brg1 activity may need to be taken on a long-term basis to suppress Brg1 and keep the heart from re-developing hypertrophy," he added.

Chang noted an important difference between humans and mice is that humans – whose heart beats at a much more leisurely 60-95 beats per minute – normally express more beta-MHC than mice in the first place. But in humans, too, Brg1 expression and the ratio of beta- to alpha-MHC increases in response to stress, which suggested that inhibiting Brg1 could be helpful in people as well.

Chang also noted that some of the experiments his team conducted suggested another role for Brg1 as well. When his team knocked out Brg1 in embryos, they died because cardiac stem cells stopped proliferating and turned into specific cell types.

In other words, "Brf1 is required for keeping cardiomyocytes in an embryonic state," he said. These findings were not the focus of the paper. But from a regenerative medicine point of view, it is information that might come in handy.