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 potentially fatal heart disease LQT-2, which is characterized by the prolongation of a specific interval of time (known as the QT interval) in the heart’s electrical cycle, is caused by mutations in the HERG gene. What triggers the changes in the electrical activity in the heart (and therefore in the beating of the heart) has not been completely determined, although loud noises and emotional stress can be triggers. In a new study, a team of researchers from the Academic Medical Centre, The Netherlands, and the University of Wisconsin, Madison, has revealed that fever can also trigger life-threatening changes in the electrical activity in the heart of patients with LQT-2.

The team, led by Arthur Wilde and Craig January, measured the electrical activity in the heart over time (something that is recorded in an ECG) of two LQT-2 patients with the same HERG mutation (A558P), and found that fever was associated with prolonged QT intervals in these individuals. When this mutation was introduced into a cultured human cell line, the cells exhibited temperature-dependent characteristics, including altered electrical currents across their cell membranes at high temperatures. The authors therefore conclude that similar changes in electrical currents occur in heart cells at the high temperatures associated with fever and that fever is a potential trigger of the potentially lethal changes in the electrical activity in the heart of patients with LQT-2.

The workplace, in addition to being a place for making money, has the potential for making a dent in Americans’ struggles with obesity, according to Indiana University researchers. A study led by Whitney E. Hornsby, a graduate student in IU Bloomington’s School of Health Physical Education and Recreation, examined weight and activity levels of 56 people ages 23 to 61 who worked desk jobs. The study found that 80 percent of the employees were overweight or obese, which is higher than the general population, and the employees also reported a lower quality of life than the general population. “Obesity rates have increased while leisure time has stayed the same or increased,” said Jeanne Johnston, assistant professor in the School of HPER’s Department of Kinesiology. “We’re becoming more sedentary in our jobs. As technology improves, it makes it easier or requires us to be closer to our desks.”

• Background: The study, says Johnston, a co-author, is part of the IU researchers’ efforts to use the workplace to stimulate healthier behaviors. She said employee wellness programs typically come in two forms — they make available an on-site fitness facility that typically is rarely used, or they make available health and wellness assessments without the resources to help employees implement the recommended changes. The IU researchers are studying a behavioral change program designed to increase employees’ activity levels to the light and moderate range, rather than launching them into a full-scale workout regimen. “The transition is really important, getting to where people are in their stage of exercise and moving them along the continuum,” Johnston said. “I’m a big believer that we need to help people move from being sedentary to being active, where they can see the results. Then, they might be motivated to join a fitness facility.”

An Indiana University study involving college freshmen found that almost half of the students had at least two risk factors for heart disease. The study, led by Cameron L. Troxell, a graduate student in the IU Bloomington School of Health, Physical Education and Recreation, involved 101 male and female college freshmen who answered a questionnaire designed to help researchers gauge the students’ perceptions of their own health compared to the actual measurements. The study found that 30 percent of the students had high cholesterol, compared to 4 percent who self-reported this risk factor. “A lot of the students were very surprised that they had high cholesterol,” said co-author Jeanne Johnston, assistant professor in the School of HPER’s Department of Kinesiology. “It really hit home that they need to start thinking about their healthy habits and behaviors.” Johnston said the college-age population is an understudied age group but an important age group, because of the independence that occurs during this critical transition period and the potential for developing lifelong healthy habits.