Nav: Home

Temple researchers identify novel mechanism underlying efficacy of common heart failure drug

July 03, 2017

(Philadelphia, PA) - Beta-blocker drugs serve a key role in the treatment of heart failure, preventing bombardment of the heart by catecholamines - substances like epinephrine and norepinephrine - which overexcite and stress the heart. But not all heart failure patients respond to beta-blockers, for reasons that have been unclear. Now, in new work, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) show that dysfunction of beta-adrenergic receptor 3 (β3AR) - a novel beta-blocker target - and consequent decreases in a critical cardioprotective phospholipid may be to blame.

The cardioprotective molecule, known as sphingosine 1-phosphate 1 (S1P), keeps heart cells from dying following events such as heart attack and heart failure. "The higher the levels of S1P in heart failure, the better the outcome," explains Walter J. Koch, PhD, W.W. Smith Endowed Chair in Cardiovascular Medicine, Professor and Chair of the Department of Pharmacology and Director of the Center for Translational Medicine at LKSOM, as well as senior investigator on the new study.

According to Dr. Koch, beta-blocker drugs increase S1P levels by attenuating hyperactive beta-adrenergic receptor signaling, with most of the drugs acting selectively on β1ARs. "But the drugs can also have stimulatory effects on β3AR, promoting β3AR activity," he says. "Our new work shows that when β3AR is dysfunctional, the protective effects of S1P are lost."

The findings were published online July 3 in the Journal of the American College of Cardiology.

"Our group has spent more than a decade investigating beta-blocker mechanisms," explains Alessandro Cannavo, PhD, a research associate in the Center for Translational Medicine and Department of Pharmacology at LKSOM and lead author on the new report. "We know that a kinase called GRK2 that is downstream of beta-adrenergic receptor activation is responsible for downregulation (decreased production) of the S1P receptor 1 (S1PR1), which functions in cardioprotective signaling. We have also demonstrated in rats that restoration of S1PR1, via gene-therapy, can correct heart failure."

In their new study, Dr. Koch and colleagues looked more deeply into the mechanisms driving S1PR1 downregulation in heart failure, as well as the effects on S1P of metoprolol, a commonly used beta-blocker drug. Experiments in cells exposed to isoproterenol (to mimic the condition of heart failure) showed that treatment with metoprolol prevented S1PR1 downregulation. Microscopic studies revealed that whereas isoproterenol triggered S1PR1 internalization, with receptors retreating from their active front at the cell surface into the interior of the cell, metoprolol produced the opposite effect.

The researchers further showed in mice that treatment with either metoprolol or S1P effectively halts heart failure progression following heart attack. To determine whether those effects were related to β3AR, Dr. Koch's team performed a series of experiments in β3AR knockout mice. S1P levels remained low in β3AR knockout animals, despite treatment with metoprolol. Moreover, in the absence of β3AR, metoprolol failed to ameliorate cardiac damage suffered post-heart attack, whereas metoprolol improved cardiac function after heart attack in mice with normal β3AR expression.

Analyses of samples from heart failure patients taking β1AR blockers confirmed the clinical relevance of the findings. Compared to untreated patients, circulating levels of S1P were significantly elevated in patients that had been treated with the drugs.

"In the concept of precision medicine, our study suggests that altered β3AR or S1P signaling can be responsible for the diverse response to beta-blockers between human patients usually observed in clinical practice," says Dr. Cannavo.

"Mechanistically, we've identified a novel means by which β1AR blockers prevent the progression of heart failure, whereby β3AR must be active for metoprolol to work," adds Dr. Koch.

The team plans next to explore the effects of beta-blockers that lack activity at β3AR.
-end-
Other investigators contributing to the new study include Giuseppe Rengo and Nicola Ferrara, Department of Translational Medical Science, University of Naples Federico II, Italy, and Istituti Clinici Scientifici Maugeri SpA Società Benefit, Telese Terme Institute (BN), Italy; Daniela Liccardo, Ehre Gao, and Alvin J. George, Center for Translational Medicine and Department of Pharmacology, LKSOM; Andres Pun, Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC); Giuseppina Gambino and Dario Leosco, Department of Translational Medical Science, University of Naples Federico II; Antonio Rapacciuolo, Department of Advanced Medical Science, University of Naples Federico II; Borja Ibanez, Myocardial Pathophysiology Area at CNIC, IIS-Fundacio?n Jime?nez Di?az in Madid, Spain, and CIBER de Enfermedades Cardiovasculares (CIBERCV); and Nazareno Paolocci, Dipartimento di Medicina Sperimentale, Universita' degli Studi di Perugia, Perugia, Italy, and Division of Cardiology, Johns Hopkins University Medical Institutions, Baltimore.

The research was funded in part by National Institutes of Health grants R37 HL061690, RO1 HL088503, P01 HL08806, P01 HL075443, P01 HK091799, and RO1 HL063030.

About Temple Health

Temple University Health System (TUHS) is a $1.6 billion academic health system dedicated to providing access to quality patient care and supporting excellence in medical education and research. The Health System consists of Temple University Hospital (TUH), ranked among the "Best Hospitals" in the region by U.S. News & World Report; TUH-Episcopal Campus; TUH-Northeastern Campus; Fox Chase Cancer Center, an NCI-designated comprehensive cancer center; Jeanes Hospital, a community-based hospital offering medical, surgical and emergency services; Temple Transport Team, a ground and air-ambulance company; and Temple Physicians, Inc., a network of community-based specialty and primary-care physician practices. TUHS is affiliated with the Lewis Katz School of Medicine at Temple University.

The Lewis Katz School of Medicine (LKSOM), established in 1901, is one of the nation's leading medical schools. Each year, the School of Medicine educates approximately 840 medical students and 140 graduate students. Based on its level of funding from the National Institutes of Health, the Katz School of Medicine is the second-highest ranked medical school in Philadelphia and the third-highest in the Commonwealth of Pennsylvania. According to U.S. News & World Report, LKSOM is among the top 10 most applied-to medical schools in the nation.

Temple Health refers to the health, education and research activities carried out by the affiliates of Temple University Health System (TUHS) and by the Katz School of Medicine. TUHS neither provides nor controls the provision of health care. All health care is provided by its member organizations or independent health care providers affiliated with TUHS member organizations. Each TUHS member organization is owned and operated pursuant to its governing documents.

Temple University Health System

Related Heart Failure Articles:

Top Science Tip Sheet on heart failure, heart muscle cells, heart attack and atrial fibrillation results
Newly discovered pathway may have potential for treating heart failure - New research model helps predict heart muscle cells' impact on heart function after injury - New mass spectrometry approach generates libraries of glycans in human heart tissue - Understanding heart damage after heart attack and treatment may provide clues for prevention - Understanding atrial fibrillation's effects on heart cells may help find treatments - New research may lead to therapy for heart failure caused by ICI cancer medication
Machining the heart: New predictor for helping to beat chronic heart failure
Researchers from Kanazawa University have used machine learning to predict which classes of chronic heart failure patients are most likely to experience heart failure death, and which are most likely to develop an arrhythmic death or sudden cardiac death.
Heart attacks, heart failure, stroke: COVID-19's dangerous cardiovascular complications
A new guide from emergency medicine doctors details the potentially deadly cardiovascular complications COVID-19 can cause.
Autoimmunity-associated heart dilation tied to heart-failure risk in type 1 diabetes
In people with type 1 diabetes without known cardiovascular disease, the presence of autoantibodies against heart muscle proteins was associated with cardiac magnetic resonance (CMR) imaging evidence of increased volume of the left ventricle (the heart's main pumping chamber), increased muscle mass, and reduced pumping function (ejection fraction), features that are associated with higher risk of failure in the general population
Transcendental Meditation prevents abnormal enlargement of the heart, reduces chronic heart failure
A randomized controlled study recently published in the Hypertension issue of Ethnicity & Disease found the Transcendental Meditation (TM) technique helps prevent abnormal enlargement of the heart compared to health education (HE) controls.
Beta blocker use identified as hospitalization risk factor in 'stiff heart' heart failure
A new study links the use of beta-blockers to heart failure hospitalizations among those with the common 'stiff heart' heart failure subtype.
Type 2 diabetes may affect heart structure and increase complications and death among heart failure patients of Asian ethnicity
The combination of heart failure and Type 2 diabetes can lead to structural changes in the heart, poorer quality of life and increased risk of death, according to a multi-country study in Asia.
Preventive drug therapy may increase right-sided heart failure risk in patients who receive heart devices
Patients treated preemptively with drugs to reduce the risk of right-sided heart failure after heart device implantation may experience the opposite effect and develop heart failure and post-operative bleeding more often than patients not receiving the drugs.
How the enzyme lipoxygenase drives heart failure after heart attacks
Heart failure after a heart attack is a global epidemic leading to heart failure pathology.
Novel heart pump shows superior outcomes in advanced heart failure
Severely ill patients with advanced heart failure who received a novel heart pump -- the HeartMate 3 left ventricular assist device (LVAD) -- suffered significantly fewer strokes, pump-related blood clots and bleeding episodes after two years, compared with similar patients who received an older, more established pump, according to research presented at the American College of Cardiology's 68th Annual Scientific Session.
More Heart Failure News and Heart Failure Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Sound And Silence
Sound surrounds us, from cacophony even to silence. But depending on how we hear, the world can be a different auditory experience for each of us. This hour, TED speakers explore the science of sound. Guests on the show include NPR All Things Considered host Mary Louise Kelly, neuroscientist Jim Hudspeth, writer Rebecca Knill, and sound designer Dallas Taylor.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

Kittens Kick The Giggly Blue Robot All Summer
With the recent passing of Ruth Bader Ginsburg, there's been a lot of debate about how much power the Supreme Court should really have. We think of the Supreme Court justices as all-powerful beings, issuing momentous rulings from on high. But they haven't always been so, you know, supreme. On this episode, we go all the way back to the case that, in a lot of ways, started it all.  Support Radiolab by becoming a member today at Radiolab.org/donate.