Tag: Internal Medicine (Cardiology)

In the NIH-funded study, published in the Journal of Cardiac Failure, the team found that thyroid hormone replacement therapy significantly reduced the incidence of atrial fibrillation — a specific kind of irregular heartbeat, or arrhythmia — in the rats, compared to a control group that did not receive the hormones. The finding could have important implications for future treatment of human patients, says lead researcher Youhua Zhang, MD, Ph.D., noting that up to about half of the humans with heart failure also suffer from atrial fibrillation. “Our data highlights the potential clinical importance of correcting thyroid dysfunction to prevent cardiac arrhythmias and atrial fibrillation in heart failure,” Zhang and the researchers wrote in their study. “In other words, withholding thyroid hormone treatment in heart failure may do harm when cardiac hormone levels are below normal.” Zhang said researchers induced heart attacks in a group of 29 rats. Fourteen were treated with a form of — thyroid hormone known as T4. After two months of treatment, the researchers measured cardiac function and then attempted to induce rapid and irregular heartbeats. Eleven of the 15 animals in the control group developed the arrhythmia but only four of the 14 animals treated with the thyroid hormone developed an arrhythmia. “When you treat these animals with myocardial infarctions, they are more resistant to developing arrhythmias,” Zhang said. Zhang’s study builds upon previous studies conducted at NYIT that demonstrate links between thyroid hormones and heart health in animal models. Five months ago, Zhang’s collaborator A. Martin Gerdes, Ph.D., published a study in Molecular Medicine that found administering low doses of the active form of the thyroid hormone known as T3 prevented the development of heart disease in rats with diabetes. Previously, Gerdes has published studies demonstrating that hypertension and heart attacks also trigger low cardiac thyroid hormone levels and contribute to heart disease. Gerdes and Zhang believe that human clinical trials involving patients with heart failure may lead to findings that radically change heart failure treatment protocols. The current study notes reluctance to use thyroid hormone replacement therapy in humans with heart diseases likely has its roots in several studies that used excessive doses of thyroid hormones or thyroid mimics.

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2014/12/141210140838.htm  Original web page at Science Daily

A team of researchers led by the University of Pennsylvania School of Veterinary Medicine’s Kendra K. Bence have now drawn connections between known regulators of body mass, pointing to possible treatments for obesity and metabolic disorders. Their work also presents intriguing clues that these same molecular pathways may play a role in learning and perhaps even in some forms of brain cancer. Bence, an associate professor in the Department of Animal Biology at Penn Vet, was senior author on the work, which was published in the Journal of Biological Chemistry. Her collaborators included lead author and neuroscience doctoral student Ceren Ozek and Harvey J. Grill, a professor in Penn’s Department of Psychology in the School of Arts & Sciences. The Penn researchers teamed with Scott E. Kanoski of the University of Southern California and Zhong-Yin Zhang of Indiana University. Previous research by Bence and colleagues highlighted the important role of the enzyme protein tyrosine phosphatase 1B (PTP1B) in regulating body weight. They showed that PTP1B acts to counter the action of the hormone leptin, which is produced by fat cells and suppresses appetite. When mice have been bred to lack PTP1B, they remain lean even when they have unlimited access to high-fat food. Yet other work has shown that mice lacking both leptin and PTP1B are trimmer than mice that lacked just leptin. “That nagged at us because it clearly indicates that there are other targets than just leptin signaling for this phosphatase,” Bence said. That sparked a search for these theoretical targets. The team knew that PTP1B has an affinity to recognize a particular sequence of amino acids. Looking for other proteins with this sequence, they turned up tropomyosin receptor kinase B (TrkB), a receptor in the brain that binds to a molecule called brain-derived neurotrophic factor (BDNF). “That was interesting because mutations in the BDNF gene have been found in study after study to be strongly correlated with body mass index in humans,” Bence said. To see if PTP1B does in fact act upon TrkB, the researchers first performed a series of experiments on neuronal cells in culture. They found that boosting expression of PTP1B suppressed BDNF and TrkB activity. Conversely, inhibiting PTP1B activity enhanced the activity of the BDNF-TrkB signaling pathway. The researchers also used biochemical assays to confirm that PTP1B physically interacts with TrkB. Moving to mice, Bence, Grill and colleagues gave animals bred to lack PTP1B a dose of BDNF in their brains, an action that, in normal mice, reduces appetite. Lacking PTP1B didn’t change this fact. But these mice did differ from normal mice in one important way: their core temperature. The genetically altered mice had higher core temperatures after a dose of BDNF than normal mice, an effect that correlates with increased energy expenditure — calories out — and thus causes weight loss. “This is the first time that anyone has linked PTP1B with BDNF and TrkB in vivo,” Bence said. “And it was interesting to see that the effect on weight regulation seems to be through impacting core temperature and not food consumption.” Finally, because BDNF is known to support the growth and survival of brain cells, the team examined whether PTP1B had an effect on that function. Inhibiting PTP1B in cultured neuroblastoma cells increased outgrowth of neuron projections called neuritis, a potential indicator of brain maturation and development. “This opens up really interesting new avenues for investigation,” Bence said, “because Trk receptors are critically important during neurodevelopment, particularly just before and right after birth. It could be that PTP1B and BDNF are playing a role in programming the brain’s ability to regulate body weight during a critical period of brain development.” What’s more, because BDNF is known to play a more general role in brain function, the findings suggests that PTP1B, too, may be influencing more than obesity and metabolism. Trk receptors, for example, are overrepresented in neuroblastoma, a cancer of the nerve cells that often affects children. “The most exciting thing to me is this whole new area of investigation into the role of PTP1B regulation of all the Trk receptors,” she said, an area that might include explorations of the receptors’ role in neurogenesis, learning and memory and perhaps even neuroblastoma.

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2014/11/141111142243.htm  Original web page at Science Daily

Rheumatoid arthritis is a condition that causes painful inflammation of several joints in the body. The joint capsule becomes swollen, and the disease can also destroy cartilage and bone as it progresses. Rheumatoid arthritis affects 0.5% to 1% of the world’s population. Up to this point, doctors have used various drugs to slow or stop the progression of the disease. But now, ETH Zurich researchers have developed a therapy that takes the treatment of rheumatoid arthritis in mice to a new level: after receiving the medication, researchers consider the animals to be fully cured. The drug is a biotechnologically produced active substance consisting of two fused components. One component is the body’s own immune messenger interleukin 4 (IL-4); previous studies have shown that this messenger protects mice with rheumatoid arthritis against cartilage and bone damage. ETH scientists have coupled an antibody to IL-4 that, based on the key-lock principle, binds to a form of a protein that is found only in inflamed tissue in certain diseases (and in tumour tissue). “As a result of combination with the antibody, IL-4 reaches the site of the disease when the fusion molecule is injected into the body,” says pharmacist Teresa Hemmerle, who has just completed her dissertation in the group of Dario Neri, a professor at the Institute of Pharmaceutical Sciences. Together with Fabia Doll, also a PhD pharmacist at ETH, she is the lead author of the study. “It allows us to concentrate the active substance at the site of the disease. The concentration in the rest of the body is minimal, which reduces side-effects,” she says. The researchers tested the new fusion molecule, which they refer to as an ‘armed antibody’, in a CTI project together with the ETH spin-off Philochem. They used a mouse model in which the animals developed swollen, inflamed toes and paws within a few days. Among other things, the researchers studied the fusion molecule in combination with dexamethasone, a cortisone-like anti-inflammatory drug that is already used to treat rheumatoid arthritis in humans. The researchers started treating each mouse as soon as they began showing signs of the disease in the form of swollen extremities. When used separately, the new fusion molecule and dexamethasone managed only to slow the progression of the disease in the affected animals. In contrast, the typical signs of arthritis, such as swollen toes and paws, disappeared completely within a few days when both medications were administered at the same time. Concentrations of a whole range of immune messengers in blood and inflamed tissue, which are changed in rheumatoid arthritis, returned to their normal levels. “In our mouse model, this combined treatment creates a long-term cure,” says Hemmerle, who, since completing her dissertation, has been working at Philochem, where she continues the project. Based on the promising results from the animal model, Philochem is currently preparing to test the new drug in clinical trials on people suffering from rheumatoid arthritis. According to the researchers, these tests will begin in the next year.

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2014/08/140806102806.htm  Original web page at Science Daily

Published in the Aug. 1 issue of The Journal of Clinical Investigation (JCI), the study showed that when the researchers blocked the effects of the nuclear receptor PPARgamma in a small number of brain cells in mice, the animals ate less and became resistant to a high-fat diet. “These animals ate fat and sugar, and did not gain weight, while their control littermates did,” said lead author Sabrina Diano, professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine. “We showed that the PPARgamma receptor in neurons that produce POMC could control responses to a high-fat diet without resulting in obesity.” POMC neurons are found in the hypothalamus and regulate food intake. They are the neurons that when activated make you feel full and curb appetite. PPARgamma regulates the activation of these neurons. Diano and her team studied transgenic mice that were genetically engineered to delete the PPARgamma receptor from POMC neurons. They wanted to see if they could prevent the obesity associated with a high-fat, high-sugar diet. “When we blocked PPARgamma in these hypothalamic cells, we found an increased level of free radical formation in POMC neurons, and they were more active,” said Diano, who is also professor of comparative medicine and neurobiology at Yale and director of the Reproductive Neurosciences Group. The findings also have key implications in diabetes. PPARgamma is a target of thiazolidinedione (TZD), a class of drugs used to treat type 2 diabetes. They lower blood-glucose levels, however, patients gain weight on these medications. “Our study suggests that the increased weight gain in diabetic patients treated with TZD could be due to the effect of this drug in the brain, therefore, targeting peripheral PPARgamma to treat type 2 diabetes should be done by developing TZD compounds that can’t penetrate the brain,” said Diano. “We could keep the benefits of TZD without the side-effects of weight gain. Our next steps in this research are to test this theory in diabetes mouse models.”

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2014/08/140801213521.htm  Original web page at Science Daily

While developing a new cancer drug, researchers discovered that mice lacking a specific protein live longer lives with fewer age-related illnesses. The mice, which lack the TRAP-1 protein, demonstrated less age related tissue degeneration, obesity, and spontaneous tumor formation when compared to normal mice. Their findings could change how scientists view the metabolic networks within cells. While developing a new cancer drug, researchers at The Wistar Institute discovered that mice lacking a specific protein live longer lives with fewer age-related illnesses. The mice, which lack the TRAP-1 protein, demonstrated less age-related tissue degeneration, obesity, and spontaneous tumor formation when compared to normal mice. Their findings could change how scientists view the metabolic networks within cells.

In healthy cells, TRAP-1 is an important regulator of metabolism and has been shown to regulate energy production in mitochondria, organelles that generate chemically useful energy for the cell. In the mitochondria of cancer cells, TRAP-1 is universally overproduced. The Wistar team’s report, which appears in the journal Cell Reports, shows how “knockout” mice bred to lack the TRAP-1 protein compensate for this loss by switching to alternative cellular mechanisms for making energy. “We see this astounding change in TRAP-1 knockout mice, where they show fewer signs of aging and are less likely to develop cancers,” said Dario C. Altieri. M.D., Robert and Penny Fox Distinguished Professor and director of The Wistar Institute’s National Cancer Institute-designated Cancer Center. “Our findings provide an unexpected explanation for how TRAP-1 and related proteins regulate metabolism within our cells.” “We usually link the reprogramming of metabolic pathways with human diseases, such as cancer,” Altieri said. “What we didn’t expect to see were healthier mice with fewer tumors.” Altieri and his colleagues created the TRAP-1 knockout mice as part of their ongoing investigation into their novel drug, Gamitrinib, which targets the protein in the mitochondria of tumor cells. TRAP-1 is a member of the heat shock protein 90 (HSP90) family, which are “chaperone” proteins that guide the physical formation of other proteins and serve a regulatory function within mitochondria. Tumors use HSP90 proteins, like TRAP-1, to help survive therapeutic attack.

“In tumors, the loss of TRAP-1 is devastating, triggering a host of catastrophic defects, including metabolic problems that ultimately result in the death of the tumor cells,” Altieri said. “Mice that lack TRAP-1 from the start, however, have three weeks in the womb to compensate for the loss of the protein.” The researchers found that in their knockout mice, the loss of TRAP-1 causes mitochondrial proteins to misfold, which then triggers a compensatory response that causes cells to consume more oxygen and metabolize more sugar. This causes mitochondria in knockout mice to produce deregulated levels of ATP, the chemical used as an energy source to power all the everyday molecular reactions that allow a cell to function. This increased mitochondrial activity actually creates a moderate boost in oxidative stress (“free radical damage”) and the associated DNA damage. While DNA damage may seem counterproductive to longevity and good health, the low level of DNA damage actually reduces cell proliferation — slowing growth down to allow the cell’s natural repair mechanisms to take effect. According to Altieri, their observations provide a mechanistic foundation for the role of chaperone molecules, like HSP90, in the regulation of bioenergetics in mitochondria — how cells produce and use the chemical energy they need to survive and grow. Their results explain some contradictory findings in the scientific literature regarding the regulation of bioenergetics and dramatically show how compensatory mechanisms can arise when these chaperone molecules are taken out of the equation. “Our findings strengthen the case for targeting HSP90 in tumor cells, but they also open up a fascinating array of questions that may have implications for metabolism and longevity,” Altieri said. “I predict that the TRAP-1 knockout mouse will be a valuable tool for answering these questions.”

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2014/07/140731145831.htm  Original web page at Science Daily

The link between obesity and osteoarthritis may be more than just the wear and tear on the skeleton caused by added weight. A DukeUniversity study has found that the absence of the appetite hormone leptin can determine whether obese mice experience arthritis, no matter how heavy they are. We were completely surprised to find that mice that became extremely obese had no arthritis if their bodies didn’t have leptin,” said Farshid Guilak, PhD, director of orthopaedic research in the Duke Department of Surgery. “Although there was some earlier evidence that leptin might be involved in the arthritis disease process, we didn’t think that there would be no arthritis at all.” In fact, the joints from the obese mice in the study appearing in the journal Arthritis & Rheumatism looked better than those of the normal control mice, Guilak said. “However, in another study, we found that mice that gained half as much weight on a high-fat diet but processed leptin normally showed significant knee osteoarthritis.” Leptin influences many of the factors involved in osteoarthritis — body weight, inflammation, sex hormone levels, and bone metabolism, said lead author Tim Griffin, PhD, who was at Duke Orthopaedic Department and now is an assistant member of the Free Radical Biology and Aging Program at the Oklahoma Medical Research Foundation. “That also makes leptin challenging to study, however, because it’s difficult to isolate which pathway is being altered to prevent the development of osteoarthritis.” Leptin is a well-known regulator of appetite, but this is the first time scientists have reported a role for leptin as a metabolic link between obesity and altered cartilage metabolism in joints. The role of obesity as a risk factor for arthritis is well characterized, but it was thought to be merely a case of overloading joints with extra weight. “It hadn’t been studied beyond that,” Guilak said. “We knew from other studies that obese people got arthritis in their hands, too, which don’t bear weight. This indicated that something besides just body-weight level affected their joints.”

The Duke team set out to learn whether the increased body fat of obesity causes an inflammatory response in joints — an imbalance of the immune system signaling proteins called cytokines and other chemicals in osteoarthritis. They studied mice that were leptin-deficient or deficient in leptin receptors — mice that didn’t have any effective leptin in their bodies. Both types of mice overate and gained weight. Then they compared the study mice with normal mice to document knee osteoarthritis. The measurements included pro- and anti-inflammatory cytokines present in arthritis, and several tests to assess bone changes in the knees of the mice. The knee bones of the leptin-free, obese mice did change, but without forming osteoarthritis. The levels of inflammatory cytokines, which correlate with arthritis, were largely unchanged in these mice. The results suggested that leptin may have a dual role in the development of osteoarthritis by regulating both the skeletal and immune systems. What does this mean for people? “Obesity is still the number one preventable risk factor of osteoarthritis, but now it seems body fat by itself is not what is causing it,” Guilak said. “If you are obese, there are benefits to losing weight in terms of arthritis. For example, if you are obese and lose just 10 pounds, pain decreases significantly. Pain modulation is another clue it might be a chemical or systemic metabolic effect, rather than just a mechanical effect of less weight on the joints.” As with many studies that yield unanticipated findings, “we have a lot of additional questions and experiments that need to be done. “With obesity and osteoarthritis, there are good similarities between humans and mice,” Guilak said. “If we can find a pathway that links a high-fat diet with arthritis, then we can try to identify and block the inflammatory mediators that are linked with the dietary fat.”

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2014/07/140711101555.htm  Original web page at Science Daily

In mice with diet-induced diabetes — the equivalent of type 2 diabetes in humans — a single injection of the protein FGF1 is enough to restore blood sugar levels to a healthy range for more than two days. The discovery by Salk scientists, published today in the journal Nature, could lead to a new generation of safer, more effective diabetes drugs. The team found that sustained treatment with the protein doesn’t merely keep blood sugar under control, but also reverses insulin insensitivity, the underlying physiological cause of diabetes. Equally exciting, the newly developed treatment doesn’t result in side effects common to most current diabetes treatments. “Controlling glucose is a dominant problem in our society,” says Ronald M. Evans, director of Salk’s Gene Expression Laboratory and corresponding author of the paper. “And FGF1 offers a new method to control glucose in a powerful and unexpected way.” Type 2 diabetes, which can be brought on by excess weight and inactivity, has skyrocketed over the past few decades in the United States and around the world. Almost 30 million Americans are estimated to have the disease, where glucose builds up in the bloodstream because not enough sugar-carting insulin is produced or because cells have become insulin-resistant, ignoring signals to absorb sugar. As a chronic disease, diabetes can cause serious health problems and has no specific cure. Rather it is managed — with varying levels of success — through a combination of diet, exercise and pharmaceuticals. Diabetes drugs currently on the market aim to boost insulin levels and reverse insulin resistance by changing expression levels of genes to lower glucose levels in the blood. But drugs, such as Byetta, which increase the body’s production of insulin, can cause glucose levels to dip too low and lead to life-threatening hypoglycemia, as well as other side effects. In 2012, Evans and his colleagues discovered that a long-ignored growth factor had a hidden function: it helps the body respond to insulin. Unexpectedly, mice lacking the growth factor, called FGF1, quickly develop diabetes when placed on a high-fat diet, a finding suggesting that FGF1 played a key role in managing blood glucose levels. This led the researchers to wonder whether providing extra FGF1 to diabetic mice could affect symptoms of the disease.

Evans’ team injected doses of FGF1 into obese mice with diabetes to assess the protein’s potential impact on metabolism. Researchers were stunned by what happened: they found that with a single dose, blood sugar levels quickly dropped to normal levels in all the diabetic mice. “Many previous studies that injected FGF1 showed no effect on healthy mice,” says Michael Downes, a senior staff scientist and co-corresponding author of the new work. “However, when we injected it into a diabetic mouse, we saw a dramatic improvement in glucose.” The researchers found that the FGF1 treatment had a number of advantages over the diabetes drug Actos, which is associated with side effects ranging from unwanted weight gain to dangerous heart and liver problems. Importantly, FGF1 — even at high doses — did not trigger these side effects or cause glucose levels to drop to dangerously low levels, a risk factor associated with many glucose-lowering agents. Instead, the injections restored the body’s own ability to naturally regulate insulin and blood sugar levels, keeping glucose amounts within a safe range — effectively reversing the core symptoms of diabetes. “With FGF1, we really haven’t seen hypoglycemia or other common side effects,” says Salk postdoctoral research fellow Jae Myoung Suh, a member of Evans’ lab and first author of the new paper. “It may be that FGF1 leads to a more ‘normal’ type of response compared to other drugs because it metabolizes quickly in the body and targets certain cell types.” The mechanism of FGF1 still isn’t fully understood — nor is the mechanism of insulin resistance — but Evans’ group discovered that the protein’s ability to stimulate growth is independent of its effect on glucose, bringing the protein a step closer to therapeutic use. There are many questions that emerge from this work and the avenues for investigating FGF1 in diabetes and metabolism are now wide open,” Evans says. Pinning down the signaling pathways and receptors that FGF1 interacts with is one of the first questions he’d like to address. He’s also planning human trials of FGF1 with collaborators, but it will take time to fine-tune the protein into a therapeutic drug.

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2014/07/140716131541.htm Original web page at Science Daily

There’s a reason people say “Calm down or you’re going to have a heart attack.” Chronic stress—such as that brought on by job, money, or relationship troubles—is suspected to increase the risk of a heart attack. Now, researchers studying harried medical residents and harassed rodents have offered an explanation for how, at a physiological level, long-term stress can endanger the cardiovascular system. It revolves around immune cells that circulate in the blood, they propose. The new finding is “surprising,” says physician and atherosclerosis researcher Alan Tall of Columbia University, who was not involved in the new study. “The idea has been out there that chronic psychosocial stress is associated with increased cardiovascular disease in humans, but what’s been lacking is a mechanism,” he notes. Epidemiological studies have shown that people who face many stressors—from those who survive natural disasters to those who work long hours—are more likely to develop atherosclerosis, the accumulation of fatty plaques inside blood vessels. In addition to fats and cholesterols, the plaques contain monocytes and neutrophils, immune cells that cause inflammation in the walls of blood vessels. And when the plaques break loose from the walls where they’re lodged, they can cause more extreme blockages elsewhere—leading to a stroke or heart attack. Studying the effect of stressful intensive care unit (ICU) shifts on medical residents, biologist Matthias Nahrendorf of Harvard Medical School in Boston recently found that blood samples taken when the doctors were most stressed out had the highest levels of neutrophils and monocytes. To probe whether these white blood cells, or leukocytes, are the missing link between stress and atherosclerosis, he and his colleagues turned to experiments on mice. Nahrendorf’s team exposed mice for up to 6 weeks to stressful situations, including tilting their cages, rapidly alternating light with darkness, or regularly switching the mice between isolation and crowded quarters. Compared with control mice, the stressed mice—like stressed doctors—had increased levels of neutrophils and monocytes in their blood.

The researchers then homed in on an explanation for the higher levels of immune cells. They already knew that chronic stress increases blood concentrations of the hormone noradrenaline; noradrenaline, Nahrendorf discovered, binds to a cell surface receptor protein called β3 on stem cells in the bone marrow. In turn, the chemical environment of the bone marrow changes and there’s an increase in the activity of the white blood cells produced by the stem cells. “It makes sense that stress wakes up these immune cells because an enlarged production of leukocytes prepares you for danger, such as in a fight, where you might be injured,” Nahrendorf says. “But chronic stress is a different story—there’s no wound to heal and no infection.” In mice living with chronic stress, Nahrendorf’s team reported today in Nature Medicine, atherosclerotic plaques more closely resemble plaques known to be most at risk of rupturing and causing a heart attack or stroke. When the scientists blocked the β3 receptor, though, stressed mice not only had fewer of these dangerous plaques, but also had reduced levels of the active immune cells in their plaques, pinpointing β3 as a key link between stress and atherosclerosis. The finding could lead to new drugs to help prevent cardiovascular disease, suggests biologist Lynn Hedrick of the La Jolla Institute for Allergy and Immunology in San Diego, California. “I think this gives us a really direct hint that the β3 receptor is important in regulating the stress-induced response by the bone marrow,” Hedrick says. “If we can develop a drug that targets the receptor, this may be very clinically relevant.” More immediately, the new observations suggest a way that clinicians could screen patients for their risk of atherosclerosis, heart attack, and stroke, Tall says. “Rather than asking four questions about stress levels, we could use their white blood cell counts to monitor psychosocial stress,” he says.

http://www.sciencemag.org/  Science Magazine

July 22, 2014

http://news.sciencemag.org/biology/2014/06/how-stress-can-clog-your-arteries?rss=1  Original web page at Science Magazine

The entire heart muscle in young children may hold untapped potential for regeneration, new research suggests. For decades, scientists believed that after a child’s first few days of life, cardiac muscle cells did not divide. Instead, the assumption was that the heart could only grow by having the muscle cells become larger. Cracks were already appearing in that theory. But new findings in mice, scheduled for publication in Cell, provide a dramatic counterexample — with implications for the treatment of congenital heart disorders in humans. Researchers at Emory University School of Medicine have discovered that in young mice 15 days old, cardiac muscle cells undergo a precisely timed spurt of cell division lasting around a day. The total number of cardiac muscle cells increases by about 40 percent during this time, when the rest of the body is growing rapidly. [A 15-day-old mouse is roughly comparable to a child in kindergarten; puberty occurs at day 30-35 in mice.] The burst of cell division is driven by a surge of thyroid hormone, the researchers found. This suggests that thyroid hormone could aid in the treatment of children with congenital heart defects. In fact, doctors have already tested thyroid hormone supplementation in this setting on a small scale. The findings also have broader hints for researchers developing therapies for the heart. Activating the regenerative potential of the muscle cells themselves is a strategy that is an alternative to focusing on the heart’s stem cells, says senior author Ahsan Husain, PhD, professor of medicine (cardiology) at Emory University School of Medicine. “It’s not as dramatic as in fish or amphibians, but we can show that in young mice, the entire heart is capable of regeneration, not just the stem cells,” he says. The Emory researchers collaborated with Robert Graham, MD, executive director of the Victor Change Cardiac Research Institute in Australia. Co-first authors of the paper are Nawazish Naqvi, PhD, assistant professor of medicine at Emory and Ming Li, PhD, at Victor Chang.

The researchers tested how much mice, at the age of day 15, can recover from the blockage of a coronary artery. Consistent with previous research, newborn (day 2) mice showed a high level of repair after such an injury, but at day 21, they did not. The day 15 mice recovered more than the day 21 mice, indicating that some repair is still possible at day 15. The discovery came unexpectedly during the course of Naqvi and Husain’s investigation of the role of the gene c-kit — an important marker for stem cells — in cardiac muscle growth. Adult mice with a disabled c-kit gene in the heart have more cardiac muscle cells. The researchers wanted to know: when does this difference appear? “We started counting the cardiomyocyte cell numbers from birth until puberty,” Naqvi says. “It was a fascinating thing, to see the numbers increasing so sharply on one day.” It turns out that c-kit-deficient and wild-type mice both have a spurt of proliferation; the differences between them appear later. “Probably, previous investigators did not see this burst of growth because they were not looking for it,” Husain says. “It occurs during a very limited time period.” Even if in humans, the proliferation of cardiac muscle cells does not take place in such a tight time period as it does in mice, the finding is still relevant for human medicine, he says. “Cardiomyocyte proliferation is happening long after the immediate postnatal period,” Husain says. “And cells that were once thought incapable of dividing are the ones doing it.” Naqvi and Husain plan to continue to investigate the relationships between thyroid hormone, nutrition during early life, and cardiac muscle growth.

http://www.sciencedaily.com/ Science Daily

June 10, 2014

http://www.sciencedaily.com/releases/2014/05/140508121351.htm  Original web page at Science Daily

In a series of experiments, the Johns Hopkins team says it identified and halted the action of a single molecular culprit responsible for a range of biological glitches that affect the body’s ability to properly use, transport and purge itself of cholesterol — the fatty substance that accumulates inside vessels and fuels heart disease. Working with mice and rabbits, Johns Hopkins scientists have found a way to block abnormal cholesterol production, transport and breakdown, successfully preventing the development of atherosclerosis, the main cause of heart attacks and strokes and the number-one cause of death among humans. The condition develops when fat builds inside blood vessels over time and renders them stiff, narrowed and hardened, greatly reducing their ability to feed oxygen-rich blood to the heart muscle and the brain. In a series of experiments, described April 7 in the journal Circulation, the Johns Hopkins team says it identified and halted the action of a single molecular culprit responsible for a range of biological glitches that affect the body’s ability to properly use, transport and purge itself of cholesterol — the fatty substance that accumulates inside vessels and fuels heart disease. The offender, the researchers say, is a fat-and-sugar molecule called glycosphingolipid, or GSL, which resides in the membranes of all cells, and is mostly known for regulating cell growth. Results of the experiments, the scientists say, reveal that this very same molecule also regulates the way the body handles cholesterol.

The Johns Hopkins team used an existing human-made compound called D-PDMP to block the synthesis of the GSL molecule, and by doing so, prevented the development of heart disease in mice and rabbits fed a high-fat, cholesterol-laden diet. The findings reveal that D-PDMP appears to work by interfering with a constellation of genetic pathways that regulate fat metabolism on multiple fronts — from the way cells derive and absorb cholesterol from food, to the way cholesterol is transported to tissues and organs and is then broken down by the liver and excreted from the body. “Current cholesterol-lowering medications tackle the problem on a single front — either by blocking cholesterol synthesis or by preventing the body from absorbing too much of it,” says lead investigator Subroto Chatterjee, Ph.D., a cardio-metabolic expert at the Johns Hopkins Children’s Center. “But atherosclerosis is a multi-factorial problem that requires hitting the abnormal cholesterol cycle at many points. By inhibiting the synthesis of GSL, we believe we have achieved exactly that.” Specifically, the experiments showed that treatment with D-PDMP led to: a drop in the animals’ levels of so-called bad cholesterol or low-density lipoprotein, LDL; a drop in oxidized LDL, a particularly virulent form of fat that forms when LDL encounters free radicals. Oxidized LDL easily sticks to the walls of blood vessels, where it ignites inflammation, damaging the vessel walls and promoting the growth of fatty plaque; a surge in good cholesterol or high-density lipoprotein, HDL, known to counteract the effects of LDL by mopping it up; and a significant drop in triglycerides, another type of plaque-building fat.

The treatment also prevented fatty plaque and calcium deposits from building up inside the animals’ vessels. These effects were observed in animals on a daily D-PDMP treatment even though they ate a diet made up of 20 percent triglycerides — the human equivalent of eating a greasy burger for breakfast, lunch and dinner. In addition, the researchers say, D-PDMP appears to precision-target the worst byproducts of aberrant cell growth signaling, such as oxidized LDL and the activity of certain chemicals that fuel vessel inflammation, without altering cell growth itself. D-PDMP, which is already widely used in basic research to experimentally block and study cell growth and other basic cell functions, is deemed safe in animals, the investigators say. For example, animals in the current study had no side effects even when given D-PDMP doses 10 times higher than the minimum effective dose, the study found. The research team is currently designing a compound drug with D-PDMP, which they soon plan to test in other animals and, eventually, in humans. Mice used in the experiments were genetically engineered to lack a protein essential in the breakdown of fats and thus were predisposed to atherosclerosis. The researchers fed the animals a high-fat diet over the course of several months, but also gave a third of the animals a low-dose of D-PDMP. They gave a double dose of the same inhibitor to another third and placebo to the rest.

When scientists measured the thickness of the animals’ aortas — the body’s largest vessel and one that carries blood from the heart to the rest of the body — they found striking differences among the groups. As expected, the aortas of mice that got placebo had grown thicker from the accumulation of fat and calcium deposits inside them. The aortas of mice on low-dose D-PDMP, however, were significantly thinner with little to no obstruction. To the researchers’ surprise, Chatterjee says, mice eating high-fat foods and treated with high-dose D-PDMP had nearly pristine arteries free of obstruction, indistinguishable from those of healthy mice. Next, the researchers measured how well and how fast blood traveled through the animals’ blood vessels. Slower blood flow signals clogging of the vessel and is a marker of atherosclerosis. The vessels of mice fed a high-fat diet plus D-PDMP had normal blood flow. Mice receiving a high-fat diet without D-PDMP predictably had compromised blood flow. When researchers examined cells from the animals’ livers — the main site of fat synthesis and breakdown — they noticed marked differences in the expression of several genes that regulate cholesterol metabolism. The activity of these genes is heralded by the levels of enzymes they produce, Chatterjee says. Mice treated with D-PDMP had notably higher levels of two enzymes responsible for maintaining the body’s delicate fat homeostasis by regulating the way cells take in and break down cholesterol. Specifically, the scientists say, the inhibitor appeared to stimulate the action and efficacy of a class of protein pumps in the cell responsible for maintaining healthy cholesterol levels by transporting cholesterol in and out of the bloodstream. In addition, mice treated that way had higher levels of lipoprotein lipase, an enzyme responsible for the breakdown of triglycerides. A deficiency in this enzyme causes dangerous buildup of blood triglycerides.

Treatment with a D-PDMP also boosted the activity of an enzyme responsible for purging the body of fats by converting these fats into bile, the fat-dissolving substance secreted by the liver. In a final set of experiments, researchers compared the effects of treatment with D-PDMP in two groups of healthy rabbits, both fed high-fat diets, with half of them receiving treatment. Rabbits that ate high-fat food alone developed all the classic signs of atherosclerosis — fatty plaque buildup in the arteries and stiff, narrowed blood vessels. Their cholesterol levels shot up 17-fold. By contrast, rabbits treated with D-PDMP never developed atherosclerosis. Their cholesterol levels also remained normal or near-normal. The World Health Organizations estimates that high cholesterol claims 2.6 million lives worldwide each year. More than 70 million Americans have high cholesterol, according to the U.S. Centers for Disease Control and Prevention. Current cholesterol-lowering drugs, such as statins, do not work in about one-third of people who take them, experts say.

http://www.sciencedaily.com/  Science Daily

May 13, 2014

http://www.sciencedaily.com/releases/2014/04/140422121001.htm  Original web page at Science Daily