A new study by researchers at Baylor College of Medicine unveils the molecular changes that underlie the devastating rhythm disorder. Atrial fibrillation (AF) is the most common arrhythmia across the globe. In 2010, the estimated number of people with the heart condition was 33.5 million, but this doesn’t include those who are asymptomatic who remain undiagnosed. Atrial fibrillation causes palpitations in the chest and could halt the heart from pumping blood efficiently. Normally, the heart contracts and relaxes to a regular beat. However, in patients with atrial fibrillation, the upper chambers or atria of the heartbeat irregularly like a quiver, rather than pumping blood effectively into the ventricles. AF is now considered a global health problem, since it contributes to the occurrence of serious complications that may lead to morbidity and mortality, including congestive heart failure, embolic stroke, and acute coronary syndrome. In the study published in the journal Circulation, the researchers wanted to determine the underlying mechanism of the pathogenesis of atrial fibrillation.
At the molecular level, calcium is essential for maintaining a healthy heartbeat. It is known that abnormal calcium release from the sarcoplasmic reticulum contributes to the development of AD. Proper contraction and relaxation of the heart depend on the coordinated flux of calcium ions in and out of individual cardiac muscle cells. But, until now, the two processes, SR calcium release and reuptake, were thought to be mediated by separate systems. The study, however, points out changes in the current model. In the study, the researchers discovered two essential protein machines, a calcium release channel, and a calcium reuptake pump, which are all regulated by the same molecular mechanism in heart cells. To land to their findings, the team studied the molecular players in the regulation of SR calcium cycling. Using complexome profiling, the team discovered that a phosphate regulatory subunit, called PPP1R3A. This connects to both the SR calcium release and reuptake complexes. As a result, they form one unit, a super-complex, that is present in atrial cells.
To land to their findings, the team studied the molecular players in the regulation of SR calcium cycling. Using complexome profiling, the team discovered that a phosphate regulatory subunit, called PPP1R3A. This connects to both the SR calcium release and reuptake complexes. As a result, they form one unit, a super-complex, that is present in atrial cells. To confirm their finding, they used STimulated Emission Depletion, a novel imaging procedure. They were able to see the two complexes are near each other.The researchers conclude that PPP1R3A could be one of the molecular controllers that helps maintain the integrity of the new super-complex. In fact, when the team tried to delete of the PPP1R3A in mice altered the formation of the super-complex, which led to an abnormal SR calcium cycling, increasing the vulnerability to having AF. They also found that the PPP1R3A levels were reduced in patients with atrial fibrillation. The discovery could later provide new information for the development of new therapies and treatment choices for atrial fibrillation.
And from fibrillation we shift to heart attack. Without oxygen supplied by blood flow, heart cells die fast. But while a heart attack may only reduce blood and oxygen to an isolated section of heart cells, causing what’s called hypoxic ischemic injury those dying cells send signals to their neighbors. Robert Gourdie, director, Fralin Biomedical Research Institute, VTC Center for Heart and Reparative Medicine Research, who is also the Commonwealth Research Commercialization Fund Eminent Scholar in Heart Regenerative Medicine Research, commented: “The problem is that the area of dying tissue is not quarantined. Damaged heart cells start to send out signals to otherwise healthy cells, and the injury becomes much bigger. We sometimes call this spread of injury signals to nearby healthy tissues a “bystander effect”. But what if there were a way to keep the injury localized to the group of cells that are directly affected by the hypoxic ischemic injury, while allowing the nearby heart muscle cells to remain intact? Now, imagine there were a drug that you could take soon after a heart attack that could reduce damage by protecting healthy heart muscle tissue.
A study published in the Journal of the American Heart Association reveals that a new molecule developed by a team of researchers led by Dr. Gourdie could help preserve heart tissue during, and even after, a heart attack. Nearly a decade ago Dr. Gourdie and his team stumbled across a discovery. They discovered a compound that targets the activity of channels in cell membranes responsible for controlling key aspects of the bystander effect. But the compound, called alphaCT1, also had other unexpected and beneficial effects, particularly in relation to skin wound healing. They found that it helped reduce inflammation, helped heal chronic wounds such as diabetic foot ulcers. Recognizing the compound’s potential, Drs. Gourdie and Ghatnekar founded a company, FirstString Research Inc., to commercialize alphaCT1 peptide, which is now in phase III clinical trials for treating wounds. Meanwhile, Gourdie has been trying to understand how the drug works on a molecular level, which led to this last publication. But how does this peptide drug actually work?
The group designed molecules with slight chemical differences from the parent molecule, which led to an unexpected discovery. One of the alphaCT1 variants, called alphaCT11, showed more potency than the parent molecule. The researchers perfused isolated laboratory mouse hearts, keeping the organ alive and beating for a number of hours. AlphaCT11 seems to be even more effective than the original peptide in protecting hearts from ischemic injury similar to those occurring during a heart attack. The study reveals that alphaCT11 gives a robust injury-reducing effect, even when given 20 minutes after the loss of blood flow that causes ischemic injury. When put to the same test, the parent peptide did not appear to provide a heart-protective effect when administered after ischemic injury. Ongoing studies, through collaboration with Drs. Antonio Abbate and Stefano Toldo at the Virginia Commonwealth University, will examine how alphaCT11 performs in live mice. They think that AlphaCT11 could provide the basis for a new way to treat heart attacks and prevent the spread of damage that occurs immediately after.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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