cardiac dysfunction Archives - Sanford Burnham Prebys

Tag: cardiac dysfunction

Institute News

“Flying” high to understand what happens when hearts don’t get enough oxygen

AuthorSusan Gammon
Date

October 23, 2017

Fruit Fly

A good supply of oxygen is important for the survival of tissue, but it’s especially critical for organs with high-energy demands, such as the heart. Lack of oxygen (hypoxia) can occur under a variety of conditions, including high altitude, inflammation and cardiopulmonary disorders such as heart attacks and blood clots. Understanding how the heart compensates—or doesn’t compensate—under hypoxic conditions can open avenues to find treatments for hypoxia-related cardiac diseases.

Rolf Bodmer, PhD, director and professor of the Development, Aging and Regeneration Program, and Karen Ocorr, PhD, assistant professor at SBP, study hypoxia in the Drosophila model. Drosophila, a common fruit fly about 3mm long has a heart that doesn’t look much like a human’s—it’s a long tube—but it has many of the same components and genes as a human heart, making it a very useful model to study how genes and environmental conditions affect heart function.

Bodmer and Ocorr’s new study, published in the journal Circulation Cardiovascular Genetics, looked into how hypoxia can lead to long-term heart defects in Drosophila. Their research team studied two sets of flies that underwent different hypoxia treatments: Set (1) flies were subjected to chronic hypoxia for three weeks (hypoxia-treated flies), which is about half of a fly’s life, and Set (2) flies were selected for survival in hypoxic conditions over 250 generations (hypoxia-selected) flies.

While there were some significant differences discovered in the hearts of the two sets of flies, one thing was the same—the expression profile of calcineurin genes were much lower under both conditions.

“Calcineurin is actually an enzyme that promotes the enlargement of the heart (hypertrophy) under some prolonged stress conditions,” says Bodmer. “In mammals, we knew that inhibiting calcineurin reduces the pathological condition of an enlarged heart, but we didn’t know how calcineruin worked in long-term hypoxia, where hypertrophy is a defining feature of diseases linked to chronic hypoxia, most notably known as chronic mountain sickness, which is notorious for affecting high altitude dwellers in the Andes, but surprisingly not as much in Tibet.

Using calcineurin knockdown flies, the team found that without the enzyme, hearts were impaired in normal oxygen conditions. In hypoxic conditions, the damage was even worse, suggesting a careful balance of pro- and antigrowth signaling is necessary for a well-functioning and responsive heart.

“Our study in Drosophila shows that reduced cardiac calcineurin levels cause heart defects that mimic some characteristics we see during long-term hypoxia,” explains Bodmer. “Since calcineurin genes are very similar between Drosophila and human—approximately 75% identical—we believe that reduced levels of calcineurin in mammals—including humans—may play a crucial role in the progression of heart disease during long-term hypoxia exposure, and help understand cardiac complications associated with hypoxia, including population living at high altitude.”

Institute News

Will flies help fix heart rhythm problems?

AuthorSusan Gammon
Date

July 12, 2017

Ocorr Researching the rhythms of the heart

Your heart beats about 35 million times in a single a year. That’s a whopping number of beats—each generated by electrical signals that make the heart contract. Occasionally problems with heart’s electrical system can cause irregular rhythms, or arrhythmias. Some types of arrhythmias are merely annoying; others can last long enough to affect how the heart works, or even cause sudden cardiac arrest.

Although certain arrhythmias can be successfully treated with medication, surgery and/or devices such as pacemakers, cardiac disorders and heart disease still account for more deaths than any other disease.

Finding new treatments for arrhythmias requires a deep understanding of how the heart beats, and specifically the intricate electrical system that prompts the heart to contract. It also requires a model to study. Is Drosophila melanogaster—a type of fruit fly—the answer?

Using flies to study the heart

Both the human heart and fly hearts have four chambers and both start out as linear tubes in embryos—but ours loops during development to form a more compact structure where as a the fly heart does not. Despite this structural difference there are many functional similarities between the fly and human heart.

“One of the similarities that we focus on in my lab is the way ion channels work—and don’t work—to fully understand how faulty ion channels contribute to heart arrhythmias,” says Karen Ocorr, PhD, assistant professor at SBP.

Ion channels are proteins found in cell membranes that allow specific ions such as potassium, sodium and calcium, to pass through cells. When ion currents travel into heart muscle cells, the muscle becomes depolarized, creating an electrical current that causes the heart to contract. A second set of channels are important in repolarization of the heart, which allows it to relax and refill with blood.

In her new paper published in PLOS Genetics, Ocorr describes how two repolarizing potassium ion channels called hERG and KCNQ control the rate and efficiency of fly heart contractions—similar to their role in human heart muscle. The research also shows that mutations in hERG and KCNQ lead to arrhythmias that worsen with age—as they do in humans.

“In humans, when hERG is compromised, either by drugs or inherited mutations, hearts can take longer than normal to recharge between beats, causing a potentially fatal condition called long QT syndrome. In fact, some anti-arrhythmia drugs actually cause long QT syndrome, hence the need for better, more specific therapies,” explains Ocorr.

The capacity for drugs to cause long QT syndrome has led the Food and Drug Administration (FDA) to recommend including the evaluation of new cardiac and non-cardiac drugs for this possible side effect. The FDA is the United States agency that provides licenses to market new drugs.

Interestingly, neither of the ion channels we identified in the fly heart play a major role in the adult mouse heart, ruling it out as useful model to screen for drug-related long QT effects,” says Ocorr.

“We are encouraged that Drosophila may become an easy, accurate tool to pre-clinically screen for adverse cardiac events associated new anti-arrhythmia therapies—potentially making the next drug discovery for patients happen sooner.”

Read the paper here. 

Institute News

Measuring heart toxicity of cancer drugs in a dish

AuthorJessica Moore
Date

February 22, 2017

Heart muscle cells (actin filaments in green, nuclei in blue)

A class of cancer drugs known as tyrosine kinase inhibitors (TKIs) are often damaging to the heart, sometimes to the degree that they can’t be used in patients. These toxic effects are not always predictable using current preclinical methods, so they may not be discovered until they make it to clinical trials.

New research could make it possible to tell which TKIs cause heart toxicity without putting any humans at risk. The collaborative study, involving Wesley McKeithan, a PhD student in the Sanford Burnham Prebys Medical Discovery Institute (SBP) graduate program and Mark Mercola, PhD, adjunct professor at SBP and a professor at Stanford University, used lab-grown heart muscle cells to assess the drugs’ potential to cause damaging effects.

“This new method of screening for cardiotoxicity should help pharma companies focus their efforts on TKIs that will be safe,” says Mercola, who collaborated with Joseph Wu, MD, PhD, also a professor at Stanford, on the study published in Science Translational Medicine. “That could mean better new TKIs will make it to the market, since we will be able to predict whether or not they cause heart problems early in the development process.”

TKIs with tolerable cardiac side effects, which include imatinib (Gleevec) and erlotinib (Tarceva), are widely used to treat multiple types of cancer. Because tumors often become resistant to these drugs, new compounds in this class continue to be developed to provide replacement treatments. Other TKIs can harm the heart in a variety of ways, from altering electrical patterns to causing arrhythmias, reducing pumping capacity, or even increasing risk of heart attacks.

Mercola and Wu’s team used heart muscle cells derived from induced pluripotent stem cells (iPSCs), which can be generated from adult skin or blood cells. After treating heart muscle cells with one of 21 TKIs, they assessed their survival, electrical activity, contractions (beating) and communication with adjacent cells. They used a new method for measuring heart cell contraction developed by the lab of Juan Carlos del Álamo, Ph.D., at UC San Diego to create a ‘cardiac safety index’, which correlates in vitro assay results with the drugs’ serum concentrations in humans. Importantly, the safety index values matched nicely with clinical reports on the cardiotoxicity of currently used TKIs.

The study also identified a possible way to protect heart muscle cells from impairment caused by TKIs—treating them with insulin or insulin-like growth factor. Although more research is needed, the findings suggest that it may be possible to alleviate some of the heart damage in patients receiving these chemotherapies.

Mercola adds, “By using cells derived from a broader group of individuals, this screening strategy could easily be adopted by the pharma industry to predict cardiotoxicity.”

This story is based in part on a press release from Stanford University School of Medicine.

Institute News

Doug Lewandowski, PhD, elected as a Fellow of the American Association for the Advancement of Science

AuthorJessica Moore
Date

April 28, 2016

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The director of Translational Cardiovascular Research at SBP’s Lake Nona campus was recently named a Fellow of the American Association for the Advancement of Science (AAAS). E. Douglas Lewandowski, PhD, was one of 33 scientists selected to become a AAAS fellow in the Section on Medical Sciences, recognizing his “distinguished contributions to fundamental aspects of cardiac metabolism and their implications for heart disease.” Continue reading “Doug Lewandowski, PhD, elected as a Fellow of the American Association for the Advancement of Science”

Institute News

Novel model for cardiomyopathy paves the way for new therapies

Authorsgammon
Date

May 29, 2015

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A new fruit fly model that captures key metabolic defects associated with cardiomyopathy could translate into more-effective treatments for this potentially deadly heart condition, according to a study conducted by researchers at Sanford-Burnham and the Universidad Autónoma de Madrid in Spain. The findings, published April 9 in Human Molecular Genetics, could also have broader clinical implications for human metabolic diseases affecting other organ systems such as the liver and skeletal muscle. Continue reading “Novel model for cardiomyopathy paves the way for new therapies”

Institute News

Newly discovered cell stress pathway could hold therapeutic promise for diverse diseases

AuthorGuest Blogger
Date

January 5, 2015

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This post was written by Janelle Weaver, PhD, a freelance writer.

When cells are faced with unfavorable environmental conditions, such as limited nutrient availability, the activation of adaptive stress responses can help protect them against damage or death. For example, stressed cells can maintain sufficient energy levels for survival by degrading and recycling unnecessary or dysfunctional cellular components. This survival mechanism, known as autophagy (literally, ‘self-digestion’), also plays key roles in a variety of biological processes such as development and aging, and is often perturbed in various diseases. Even though tight control of autophagy is key to survival, relatively little is known about the signaling molecules that regulate this essential process.

Sanford-Burnham researchers have made important progress in addressing this gap in knowledge by discovering that proteins called STK3 and STK4 regulate autophagy across diverse species. As reported recently in Molecular Cell, the newly identified mode of autophagy regulation could potentially have important clinical implications for the treatment of a broad range of diseases, including cancer, diabetes, Alzheimer’s disease, cardiac dysfunction, and immune-related diseases.

“Our discovery is fundamental to our molecular understanding of how autophagy is regulated,” said senior study author Malene Hansen, PhD, associate professor of the Development, Aging, and Regeneration Program at Sanford-Burnham. “Because impairment in the autophagy process has been linked to many disorders in humans, we believe that pharmacological agents targeting this novel regulatory circuit may hold great therapeutic potential.”

Critical kinases

Autophagy is a cellular recycling process involving a highly intricate and complex series of events. Cellular components such as abnormal molecules or damaged organelles are first sequestered within vesicles known as autophagosomes. These vesicles then fuse with organelles called lysosomes, which contain enzymes that break down various molecules. This fusion process results in the formation of hybrid organelles called autolysosomes, where the defective cellular components are enzymatically degraded and recycled. A protein called LC3 plays crucial roles in the formation of autophagosomes and the recruitment of dysfunctional cellular components to these vesicles. The signaling events that coordinate LC3’s various functions in autophagy have not been clear, but new research from the Hansen lab now proposes a novel and essential role for the mammalian Hippo kinases STK3 and STK4 in regulating autophagy by targeting LC3 for phosphorylation.

In their study, Hansen and her team describe that deficiency in both STK3 and STK4 impairs autophagy not just in mammalian cells, but also in nematodes and yeast. When exploring how the kinases regulate autophagy in mammalian cells, the researchers discovered that phosphorylation of LC3 by STK3 and STK4, specifically on the amino acid threonine 50, is critical for fusion between autophagosomes and lysosomes—an essential step in the autophagy process. “Collectively, the results of this study strongly support a critical and evolutionarily conserved role for STK3 and STK4 in regulating autophagy, by phosphorylating the key autophagy protein LC3, at least in mammalian cells,” Hansen said.

Killing bacteria

Previous studies have shown that STK4 also plays a role in regulating antibacterial and antiviral immunity in mammals, including humans. Moreover, autophagy is known to play a role in the clearance of intracellular pathogens. “These findings, taken together with our discovery that deficiency in STK3 and STK4 severely compromises autophagy, led us to test whether STK4 also plays a role in antimicrobial immunity through its function in autophagy,” said lead study author Deepti Wilkinson, Ph.D., a postdoctoral fellow in Hansen’s lab.

To test this notion, the researchers collaborated with Victor Nizet MD, professor of Pediatrics and Pharmacy  at UC San Diego and found that indeed mouse embryonic cells deficient in both STK3 and STK4 were unable to efficiently kill intracellular group A streptococci—bacteria known to be cleared by autophagy. However, an LC3 mutation that resulted in constant phosphorylation at threonine 50 restored the ability of the STK3/STK4-deficient cells to kill the bacteria. “This finding suggests that the same STK4-LC3 signaling pathway involved in autophagy also contributes to the response of mammalian cells to infection with intracellular pathogens and could play a role in human immune-related disease,” Wilkinson said.

Correcting defects

Moving forward, the researchers plan to further probe the molecular mechanisms by which STK3 and STK4 regulate autophagy. They will also investigate the therapeutic implications of the STK3/STK4 signaling pathway for tumor suppression as well as immune-related disorders such as bacterial and viral infections. “Understanding how autophagy works and why it sometimes stops to function optimally is essential for fighting diseases such as cancer, diabetes and neurodegeneration,” Hansen said.

“We have made a major contribution towards this endeavor by showing that STK3 and STK4 play an essential role in keeping the process of autophagy running smoothly by directly phosphorylating the key autophagy protein LC3. We hope our discoveries will lead to the development of effective drugs that can help correct autophagy defects that commonly occur in these diseases,” added Hansen.

A copy of the paper can be found at: http://www.ncbi.nlm.nih.gov/pubmed/25544559