Nav: Home

Cardioprotective effects of lysyl oxidase inhibition

March 31, 2016

Heart failure is a progressive condition, where structural and functional alterations of the ventricle limit the ability of the heart to either fill or eject blood. There are approximately 550,000 new cases of heart failure each year with a prevalence of nearly 5 million; most patients die within five years of diagnosis. A prominent characteristic of heart failure is the adverse alteration of the extracellular matrix (ECM). The heart's size, shape, and function are regulated, in part, by the composition of the ECM. The major structural component of the cardiac ECM is collagen, which is produced by fibroblasts. Lysyl oxidase (LOX), also produced by fibroblasts, is a collagen cross-linking enzyme. Cross-linking makes collagen fibrils resistant to degradation and promotes collagen deposition. Although cross-linking is necessary for normal collagen formation, increased LOX expression is associated with fibrosis in the heart. Further, cardiac LOX is elevated in failing human hearts and reduced LOX expression is associated with improved function in heart failure patients, suggesting that excess activation of LOX may play a causative role in the progression of cardiac failure.

In a study reported in the March issue of Experimental Biology and Medicine Gardner and colleagues used a rat model of volume-overload (VO)-induced heart failure to evaluate the cardioprotective effects of LOX inhibition in animals with established disease. Volume overload was surgically induced through creation of an abdominal aorto-caval fistula. Prior to LOX inhibition, rats were subjected to 8 weeks of chronic volume overload, a duration previously demonstrated to produce significant cardiac hypertrophy, ventricular dilation, and dysfunction, and collagenous ECM alterations. After 8 weeks of VO, LOX was inhibited using beta-aminoproprionitrile delivered intraperitoneally for 6 weeks, which irreversibly binds to the active site of LOX inhibiting its activity and ability to cross-link collagen. LOX inhibition partially attenuated VO-induced increases in LV hypertrophy and completely reversed VO-induced increases in interstitial myocardial collagen, and protein expression of collagens I and III. Using ultrasound echo and ventricular pressure-volume catheterization, we found that LOX inhibition partially restored both systolic and diastolic function, while having little effect on sham-operated controls. Overall, our data demonstrate the cardioprotective effects of LOX inhibition on the volume overload stressed heart, and its potential to slow or even prevent the transition to heart failure.

J.D. Gardner said "The strong cardioprotective effects and functional restoration provided by LOX inhibition in our model were surprising given that one would expect that a reduction in LOX, and thereby mature collagen, would promote further ventricular dilatation in the volume overloaded heart. However, we found that the opposite was true. Reduced LOX activity reversed cardiac fibrosis and partially restored cardiac function in rats with established cardiac dysfunction. Our findings indicate that over-activation of LOX during cardiac disease promotes progressive cardiac fibrosis and heart failure. If we can determine how excessive LOX is damaging the heart, these mechanisms could be targeted for clinical benefit. "

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine, said "Gardner et al have provided the intriguing and unexpected result that inhibiting lysyl oxidase (LOX) reversed cardiac fibrosis improving heart function. This suggests that LOX may play a key role in volume overload induced cardiac dysfunction.
-end-


Society for Experimental Biology and Medicine

Related Heart Failure Articles:

New hope for treating heart failure
Heart failure patients who are getting by on existing drug therapies can look forward to a far more effective medicine in the next five years or so, thanks to University of Alberta researchers.
Activated T-cells drive post-heart attack heart failure
Chronic inflammation after a heart attack can promote heart failure and death.
ICU care for COPD, heart failure and heart attack may not be better
Does a stay in the intensive care unit give patients a better chance of surviving a chronic obstructive pulmonary disease (COPD) or heart failure flare-up or even a heart attack, compared with care in another type of hospital unit?
Tissue engineering advance reduces heart failure in model of heart attack
Researchers have grown heart tissue by seeding a mix of human cells onto a 1-micron-resolution scaffold made with a 3-D printer.
Smoking may lead to heart failure by thickening the heart wall
Smokers without obvious signs of heart disease were more likely than nonsmokers and former smokers to have thickened heart walls and reduced heart pumping ability.
After the heart attack: Injectable gels could prevent future heart failure (video)
During a heart attack, clots or narrowed arteries block blood flow, harming or killing cells in the heart.
Heart failure after first heart attack may increase cancer risk
People who develop heart failure after their first heart attack have a greater risk of developing cancer when compared to first-time heart attack survivors without heart failure, according to a study today in the Journal of the American College of Cardiology.
Scientists use 'virtual heart' to model heart failure
A team of researchers have created a detailed computational model of the electrophysiology of congestive heart failure, a leading cause of death.
Increase in biomarker linked with increased risk of heart disease, heart failure, death
In a study published online by JAMA Cardiology, Elizabeth Selvin, Ph.D., M.P.H., of the Johns Hopkins Bloomberg School of Public Health, Baltimore, and colleagues examined the association of six-year change in high-sensitivity cardiac troponin T with incident coronary heart disease, heart failure and all-cause mortality.
1 in 4 patients develop heart failure within 4 years of first heart attack
One in four patients develop heart failure within four years of a first heart attack, according to a study in nearly 25,000 patients presented today at Heart Failure 2016 and the 3rd World Congress on Acute Heart Failure by Dr.

Related Heart Failure Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Changing The World
What does it take to change the world for the better? This hour, TED speakers explore ideas on activism—what motivates it, why it matters, and how each of us can make a difference. Guests include civil rights activist Ruby Sales, labor leader and civil rights activist Dolores Huerta, author Jeremy Heimans, "craftivist" Sarah Corbett, and designer and futurist Angela Oguntala.
Now Playing: Science for the People

#521 The Curious Life of Krill
Krill may be one of the most abundant forms of life on our planet... but it turns out we don't know that much about them. For a create that underpins a massive ocean ecosystem and lives in our oceans in massive numbers, they're surprisingly difficult to study. We sit down and shine some light on these underappreciated crustaceans with Stephen Nicol, Adjunct Professor at the University of Tasmania, Scientific Advisor to the Association of Responsible Krill Harvesting Companies, and author of the book "The Curious Life of Krill: A Conservation Story from the Bottom of the World".