Top Stories - Cardiovascular Pathobiology

Drs. Daniel Kelly (left) and Ola Martin
Research highlights: American...

Several Sanford-Burnham investigators presented their research findings at the American Heart...

Dr. Masanobu Komatsu
CARing for pulmonary arterial...

Targeting peptides developed by Dr. Masanobu Komatsu and colleagues could be used to deliver...

Researchers in the Bodmer lab have discovered a new pathway to fat-related heart disease.
A different path to...

Fruit fly study demonstrates how lipotoxic cardiomyopathy might occur in genetically obese...

Calorie-burning brown fat (shown here) gets a boost from natriuretic peptides in the heart
Heart hormone helps shape fat...

Dr. Sheila Collins and colleagues discover that the pathway to losing fat is heavily influenced by a...

A “twisted” grand opening ceremony

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“My goal is to cure diabetes,” Steven Smith, M.D., scientific director of the Florida Hospital – Sanford-Burnham Translational Research Institute for Metabolism and Diabetes (TRI), said boldly at the opening ceremony of the TRI’s new state-of-the-art facility in downtown Orlando on March 27. “We believe that personalized medicine is our best shot at discovering cures for our most serious health problems like diabetes.”

The ceremony’s highlight was the unveiling of a spectacular nine-foot double-helix DNA structure that will be placed at the main entrance of the building, symbolizing the fundamental research being conducted at the TRI, as well as the synergies and collaborations the TRI represents. Selected board members and presenters each added one illuminated “bar,” representing a nucleotide, to the double helix.

“This is one of those rare times when the reality far exceeds the dream,” said John Reed, M.D., Ph.D., CEO of Sanford-Burnham. “The TRI is a wonderful opportunity for our organization, which will bring more and more to life our slogan From Research, the Power to Cure. We’re very excited about this opportunity to take our relationship with Florida Hospital to the next level.”

Heart hormone helps shape fat metabolism

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It’s well known that exercising reduces body weight because it draws on fat stores that muscle can burn as fuel. But a new study at Sanford-Burnham suggests that the heart also plays a role in breaking down fat. In their study, published February 6 in the Journal of Clinical Investigation, Sheila Collins, Ph.D. and colleagues detail how hormones released by the heart stimulate fat cell metabolism. These hormones turn on a molecular mechanism similar to what’s activated when the body is exposed to cold and burns fat to generate heat. This study adds another dimension to our understanding of how the body regulates fat tissue and may someday lead to new ways to manipulate the process with drugs to reduce weight in obese patients or maintain it in individuals who experience pathological weight loss during chronic heart failure.

“Exercise is always going to raise your blood pressure some, so there’s the potential that these heart hormones—called cardiac natriuretic peptides—are being released and contributing to the breakdown of fats,” said Collins, professor in the Diabetes and Obesity Research Center at Sanford-Burnham’s Lake Nona campus in Orlando and senior author of the study. “Over a period of time, natriuretic peptides could also be leading to an increase in the numbers of brown fat cells, which we know are very important for protection against diet-induced obesity, at least in laboratory experiments.”

Research highlights: American Heart Association Scientific Sessions 2011

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Several Sanford-Burnham investigators presented their research findings at the American Heart Association (AHA) Scientific Sessions 2011 on November 13-16, where more than 14,000 clinicians and researchers gathered in Orlando, Florida.

During his lecture at the Cardiovascular Seminar Series, Dr. Daniel Kelly, scientific director of Sanford-Burnham’s Lake Nona facility in Orlando, presented his laboratory’s ongoing work to determine the role of “energy starvation” in the development of heart failure. The Kelly laboratory has found that mitochondria, the cell’s energy-generating machines, becomes dysfunctional during the development of heart failure caused by common disease states such as high blood pressure and heart attacks. Dr. Kelly also presented several strategies his laboratory is pursuing to identify new drug targets to replenish mitochondria in the failing heart, including using the power of proteomics (defining the levels of all proteins operating in a cell) and metabolomics (identifying all the body’s metabolites).

New therapeutic target for heart disease

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Mitochondria are often called cellular “powerhouses” because they convert nutrients into energy. But these tiny structures also help determine cellular lifespan. Scientists are now discovering how mitochondria alternate between duplicating and fragmenting and how these events help cells adapt to diverse physiological conditions.

In a paper published November 18 in Molecular Cell, a team led by Dr. Ze’ev Ronai discovered that the protein Siah2 regulates mitochondrial fragmentation under low oxygen conditions. The significance of these findings is demonstrated by the heart’s response to oxygen shortage and ischemia, the tissue damage caused by lack of oxygen, when the researchers inhibited Siah2. In cells and mice lacking the protein, heart cell death was prevented. As a result, tissue damage was reduced in a mouse model that mimics a heart attack.

CARing for pulmonary arterial hypertension

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Pulmonary arteries carry blood from the heart to the lungs, where they pick up fresh oxygen for distribution to the rest of the body. Since almost every cell in the human body needs oxygen in order to convert nutrients into energy, pulmonary artery function is crucial. Pulmonary arterial hypertension (PAH) occurs when pressure builds up in these blood vessels, impairing this function. People with PAH experience shortness of breath, fatigue and chest pain. As the condition worsens, the heart has to work harder and harder to pump blood, sometimes leading to heart failure.

Despite eight approved clinical therapies for PAH and additional therapies currently in trials, there is no cure. What’s more, current treatments don’t specifically target pulmonary arteries, which can lead to severe side effects.

Sanford-Burnham scientists, led by Drs. Masanobu Komatsu and Dr. Takeo Urakami, in collaboration with VBS Pharmaceuticals, recently discovered a peptide (a short protein) that selectively targets and penetrates lung blood vessels affected by PAH. When the team tested this peptide, called CARSKNKDC (or CAR for short) in a rodent model of PAH, it homed in on hypertensive lungs, but spared healthy lungs and other organs. CAR also accumulated in other regions of the respiratory system that play crucial roles in PAH development and progression.

Published in the June 2011 issue of the American Journal of Pathology, these findings indicate that CAR could be used to deliver therapeutic compounds and imaging probes directly to PAH lungs.

Recycled: Close to the heart

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Editor’s note: We originally ran this post last summer and it quickly became one of our most popular. In honor of my mother’s birthday, July 14, I’d like to share it with you again (with an updated picture!).

Early one morning eleven years ago, I was visiting some friends while enjoying a break from college, when my dad called to tell me that my mom had died. It was sudden and completely unexpected. She was only 46 years old, healthy and seemingly full of life. My mom just went to work one evening (alone on the late shift) and never came home. As my dad tried to explain to me at the time, she just collapsed and that was it – nobody else was there to know what really happened. It was devastating to me and my family and our lives were forever changed. Not only was she gone, but we never had much of an explanation as to why. What caused her death and could it have been prevented? This was one of the hardest parts for me as both a daughter and as a young scientist. I read the medical examiner’s report myself. It wasn’t a heart attack and it wasn’t a stroke. The cause of death was simply listed as “heart failure.”

That still frustrates me. As I’ve pointed out to countless people in the years since, with all we know about the human body, it’s surprising that cause of death can still be a mystery. “Heart failure” just seems like a catch-all phrase – an easy thing to say when there’s no other explanation. After all, isn’t that what kills us all in the end?

Personalized Medicine 101

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In 2003, the completion of the human genome project gave us an unprecedented amount of genetic information. From this, a new clinical concept is emerging: personalized medicine.Conventional medical care generalizes treatment to all patients with a particular disease. But since a disease is as individual as the person who has it, casting a wide therapeutic net has its limitations. For one, patients with a certain genetic makeup might not respond to a particular drug as well as patients with different genetics, or they might experience different side effects. As personalized medicine becomes a reality, it could rectify these less-than-ideal situations.

From the diagnostic point-of-view, personalized medicine is a shift from reactive to proactive. Based on a person’s health, genetic, and environmental profiles, doctors practicing personalized medicine could assess a patient’s risk for acquiring a genetic disease before any symptoms develop. This might allow them to target the specific genes that account for illness (the BRCA1/BRCA2 genes that predispose a woman to breast cancer, for example), incorporate a prevention strategy, and monitor those genes over time. When it comes to treatment, personalized drugs could be prescribed based on an individual’s molecular “build” and targeting treatment where it will do the most good and the least harm.

Targeting Arterial Plaque

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Atherosclerotic plaque is the fatty material that builds up on arterial walls, where it can lead to heart disease and stroke. Atherosclerosis is currently treated with dietary changes, angioplasty (which uses a balloon to move the plaque aside) or more invasive procedures. Using drugs to break up these fatty plaques would be an enticing alternative, but delivery poses a problem. How do we precisely target the therapeutic agent to the diseased areas, leaving healthy tissues unaffected?

Dr. Erkki Ruoslahti and colleagues at Sanford-Burnham and UC Santa Barbara may have found a solution. For many years, Dr. Ruoslahti has been using specially designed peptides (pieces of proteins) to target cancer and other diseases. In a paper published online on April 11 by the Proceedings of the National Academy of Sciences, the Ruoslahti lab reports the discovery of a new peptide that can guide drugs or imaging agents specifically to atherosclerotic plaques.

Blog Your Heart Out!

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February is American Heart Month and today we are joining the American Heart Association and Fitlosophy, Inc. for the 2nd annual Blog Your Heart Out Day! Here we share some of our favorite blog posts on heart disease, the leading cause of death for both men and women…

A different path to fat-related heart disease

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Heart disease is the leading cause of death for both men and women in the United States. But heart disease is more than just one disease; there are many different ‘flavors’ that can result from a heart attack, high blood pressure, diabetes or other causes. In lipotoxic cardiomyopathy, for example, heart function is disrupted by fat accumulation in heart cells. Obesity and high-fat diets are major risk factors for lipotoxic cardiomyopathy, but scientists recently unraveled an alternative pathway to lipotoxic cardiomyopathy in fruit flies – a genetic mechanism that occurs independently of a diet high in fat. Their study lays the foundation for the development of new ways to combat lipotoxic cardiomyopathy and other types of heart disease.

“It’s a well-accepted notion that if you eat too much fatty food and your body can’t metabolize it properly, you can become obese and this can lead to lipotoxic cardiomyopathy. Our study shows that there is also an alternative cause of obesity and associated heart problems – an imbalance in the fats that normally make up the basic structure of our cells,” explained Dr. Hui-Ying Lim, post-doctoral researcher and lead author of the study.

In this study, the researchers analyzed mutant fruit flies (called easily shocked mutants) that have abnormally low levels of phosphatidylethanolamine (PE), a type of fat that makes up a major component of cellular membranes in both flies and mammals. They found that these flies compensate for low PE levels by initiating a mechanism for synthesizing fat. In this mechanism, a protein called sterol regulatory element-binding protein (SREBP) turns on genes encoding metabolic enzymes that synthesize more fat.

The couch potato effect

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A surprising new model for studying muscle function was unveiled this week: the couch potato mouse. While these mice maintain normal activity and body weight, they don’t have the energy to exercise. In the December 1 issue of the journal Cell Metabolism, Dr. Daniel Kelly, Dr. Christoph Zechner and their colleagues reportwhat happens when muscle tissue lacks PGC-1, a protein coactivator that muscles need to convert fuel into energy.“Part of our interest in understanding the factors that allow muscles to exercise is the knowledge that whatever this machinery is, it becomes inactive in obesity, aging, diabetes and other chronic conditions that affect mobility,” explains Dr. Kelly, scientific director at Sanford-Burnham’s Lake Nona campus.

Normally, physical stimulation boosts PGC-1 activity in muscle cells, which switches on genes that increase fuel storage, ultimately leading to “trained” muscle (the physical condition most people hope to attain through exercise). In obese people, PGC-1 levels drop, possibly further reducing a person’s capacity to exercise – creating a vicious cycle. In this study, mice without muscle PGC-1 looked normal and walked around without difficulty, but could not run on a treadmill.

Top 10 reasons to be thankful for science

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It’s that time of year when we pause to remember what we’re thankful for. We can think of many reasons to be thankful for science. Here are the top 10:

Beacause science…
10.  says fat can be good
9. uncovers new drug targets
8. is art
7. turns disease on its head
6. finds new uses for old drugs
5. inspires kids
4. is better than science fiction
3. explains how cancer works
2. provides a “do-over”

And the #1 reason we are thankful for science? Because it saves lives (and makes them better).

Why are you thankful for Science? Please leave a comment below…and have a Happy Thanksgiving!

Another way kickboxing is good for the heart

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Dr. Barbara Ranscht is a neuroscientist. While studying brain development and cancer for more than 20 years, she has come to know a molecule called T-cadherin. This protein is anchored to the cell membrane, where it senses changes in the extracellular environment to ultimately regulate cellular motility and growth. T-cadherin has multiple functions in the nervous system, but when she first discovered this protein in the 1990s, Dr. Ranscht also noted its abundance in the heart. For many years Dr. Ranscht paid little attention to the molecular workings of the heart, preferring to stick to the mysteries of the brain. Until recently, when she came across new clues about T-cadherin and its possible role in protecting the heart from stress-induced damage. At that point, most researchers would probably have let go of the idea rather than jump into a new field.

Luckily, Dr. Ranscht goes kickboxing with her colleague, friend and heart expert, Dr. Pilar Ruiz-Lozano.

Super-sized Fruit Flies

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It’s no secret that being overweight is hard on the heart – many studies have shown that heavier people are more likely to suffer from heart disease. But why, exactly? What does fat have to do with your heart?

There are numerous causes of obesity and other risk factors for heart disease, making it difficult to tease them apart. So a team led by Drs. Sean Oldham, Rolf Bodmer and Ryan Birse created a simple model to study the genes linking high-fat diet, obesity and heart dysfunction. Using fruit flies, they discovered that a protein called TOR influences fat accumulation in the heart. Their study, published November 3 in the journal Cell Metabolism, also demonstrates that manipulating TOR protects the hearts of obese flies from damage caused by high-fat diets.

Close to the Heart

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Hello! Heather here, science writer at Sanford-Burnham and frequent contributor to Beaker. We’re going to do something a little different today. I’m still going to discuss some of the cool research going on here at Sanford-Burnham, but since it affects me personally, this time it’ll be in the context of my own story…

Early one morning eleven years ago, I was visiting some friends while enjoying a break from college, when my dad called to tell me that my mom had died. It was sudden and completely unexpected. She was only 46 years old, healthy and seemingly full of life. My mom just went to work one evening (alone on the late shift) and never came home. As my dad tried to explain to me at the time, she just collapsed and that was it – nobody else was there to know what really happened. It was devastating to me and my family and our lives were forever changed. Not only was she gone, but we never had much of an explanation as to why. What caused her death and could it have been prevented? This was one of the hardest parts for me as both a daughter and as a young scientist. I read the medical examiner’s report myself. It wasn’t a heart attack and it wasn’t a stroke. The cause of death was simply listed as ‘heart failure’.