New data, generated by David Ornitz and colleagues, at Washington University School of Medicine, St. Louis, have indicated a crucial role for signaling pathways that involve the protein sonic hedgehog in maintaining the blood vessels that supply the mouse heart and keep it beating.  These data have implications for drug development as they suggest that antagonists of hedgehog signaling pathways, such as those being developed as anticancer therapeutics, might have unwanted side effects.

In the study, mice lacking the ability to mediate hedgehog signaling in cells that form part of the blood vessels that supply the heart were found to die of heart failure.  This was because in the absence of hedgehog signaling the blood vessels of the heart were lost, meaning that the heart cells were no longer supplied with enough oxygen and died.  Although these data indicate a need for caution when developing clinical antagonists of hedgehog signaling, it is possible that the degree of inhibition needed to have a clinical effect on tumor development might not have the effect on blood vessels of the heart that completely eliminating expression of the protein does.

Researchers at the University of Cincinnati (UC) are looking for ways to reduce or prevent heart damage by starting where the problem often begins: in the genes.

Following a heart attack, cells die, causing lasting damage to the heart.

Keith Jones, PhD, a researcher in the department of pharmacology and cell biophysics, and colleagues are trying to reduce post-heart attack damage by studying the way cells die in the heart—a process controlled by transcription factors.

Transcription factors are proteins that bind to specific parts of DNA and are part of a system that controls the transfer of genetic information from DNA to RNA and then to protein.  Transfer of genetic information also plays a role in controlling the cycle of cells—from cell growth to cell death.

“We call it ‘gene regulatory therapy,’” says Jones.

So far, studies have identified the role for an important group of interacting transcription factors and the genes they regulate to determine whether cells in the heart survive or die after blood flow restriction occurs.

Often, scientists use virus-like mechanisms to transfer DNA and other nucleic acids inside the body.

The “virus” takes over other healthy cells by injecting them with its DNA.  The cells, then transformed, begin reproducing the virus’ DNA.  Eventually they swell and burst, sending multiple replicas of the virus out to conquer other cells and repeat the process.

Now, UC researchers are further investigating new, non-viral delivery mechanisms for this transfer of DNA.

“We can use non-viral delivery vehicles to transfer nucleic acids, including transcription factor decoys, to repress activation of specific transcription factors in the heart,” Jones says, adding that the researchers have made this successfully work within live animal models.  “This means we can block the activity of most transcription factors in the heart without having to make genetically engineered mice.”

Jones will be presenting these results at the International Society for Heart Research in Cincinnati, June 17-20.

He says this delivery mechanism involves flooding the cells with “decoys” which trick the transcription factors into binding to the decoys rather than to target genes, preventing them from activating those genes.

“We can use this technology to identify the target genes and then investigate the action of these genes in the biological process,” Jones says.

He says that this delivery has limitations and advantages.

“It can be used to block a factor at any point in time and is reversible,” he says.  “However, right now, a specific delivery route must be used to target the tissue or cell.”

Jones and other researchers are hoping that this new technology will allow them to directly address the effects of gene regulation in disease, as opposed to using classical drugs that treat symptoms or have significant adverse outcomes.

“So far, this seems to cause no adverse effects in animals,” he says.  “We are hopeful and are working toward pre-clinical studies.”

The increased beating of the heart that one experiences when in a stressful situation is just one part of the body’s response to stress, something often known as the “fight-or-flight response”. Another component of the fight-or-flight response is the suppression of pain, also known as stress-induced analgesia (SIA). Some of the nerves and nerve-produced peptides that are responsible for SIA have been identified, but much remains to be discovered. In a new study, a team of researchers in California, from AfaSci, Inc., Burlingame, and SRI International, Menlo Park, has revealed that nerves producing the peptide N/ORQ and nerves producing the peptide Hcrt are key in regulating SIA in mice.

The research team, which was led by Xinmin Xie and Thomas Kilduff, showed that in the brain of normal mice, Hcrt-producing nerve cells (Hcrt neurons) and N/ORQ-producing nerve cells interacted. N/ORQ affected the electrical current across Hcrt neurons and the release of neurotransmitters by these cells. Furthermore, administration of N/ORQ blocked SIA in normal mice, but this was overcome by administration of Hcrt at the same time. The authors therefore conclude that N/ORQ likely influences a variety of Hcrt-mediated processes, in addition to SIA, and suggest that these pathways might contribute to medical conditions caused by excessive stress, such as anxiety and post-traumatic stress disorder.

The world’s first optical pacemaker is described in an article published today in Optics Express, the Optical Society’s open-access journal. A team of scientists at Osaka University in Japan show that powerful, but very short, laser pulses can help control the beating of heart muscle cells.”If you put a large amount of laser power through these cells over a very short time period, you get a huge response,” says Nicholas Smith, who led the research. The laser pulses cause the release of calcium ions within the cells, Smith explains, and this action forces the cells to contract.

This technique provides a tool for controlling heart muscle cells in the laboratory, a breakthrough that may help scientists better understand the mechanism of heart muscle contraction.

One potential application of this technology is in studying uncoordinated contractions in heart muscle. Normally, heart muscle contracts in a highly coordinated fashion, and this is what allows the heart to pump blood through the vasculature. But in some people, this coordinated beating breaks down, and the heart twitches irregularly—a condition known as fibrillation.

The new laser technique may allow scientists to create a form of fibrillation in the test tube. The lasers can destabilize the beating of the cells in laboratory experiments by introducing a beat frequency in one target cell distinct from the surrounding cells. This would allow scientists to study irregular heart beats on a cellular level and screen anti-fibrillation drugs.

Outside the laboratory, exposing heart muscle cells to powerful laser pulses can have its drawbacks. Although the laser pulses last for less than a trillionth of a second, damaging effects can build up over time and this currently limits the possibility of clinical applications.