Often a precursor or companion to cardiac dysfunction, hypertrophy, or enlargement of the component cells of an organism, is also a normal part of growth. For example, as babies grow, their hearts grow, too, not because the relatively finite cardiac myocyte cells that comprise the heart muscle proliferate, but because they enlarge. But the complex process that keeps that growth in check has been a mystery, one which Bishopric’s latest study, published April 24 in EMBO Molecular Medicine, a publication of the European Molecular Biological Organization, begins to unravel.
“Other studies have found things that promote growth of the heart under stress conditions, but we found something that, in baseline conditions, is holding the heart in status quo so it’s not constantly growing. It reaches a size and then stops,” said Bishopric, who is also director of the UM/Florida Heart Research Institute Cardiovascular Genomics Laboratory. “Now we have proof that there is not only a way to turn hypertrophy on when you need it, but a mechanism that keeps it off, too. That makes this pathway a very attractive drug target.”
The study, “Repression of miR-142 by p300 and MAPK is required for survival signalling via gp130 during adaptive hypertrophy,” specifically identifies two micro ribonucleic acids (microRNAs) in cardiac myocytes that target the critical enzyme p300, a master programmer of the heart responsible for inducing hypertrophy under increased cardiac workloads.
Backed by an NIH grant and support from the Florida Heart Research Institute, Bishopric and her team found that the two microRNAs inversely regulate p300, increasing when p300 is turned off, and decreasing when the epigenetic regulator is turned on.
“When the heart is exposed to stress, there is a very rapid increase in p300 in the myocytes,” Bishopric explains. “It goes up about 50-fold and it happens within hours and stays up as long as the stress lasts, but nobody really knows what is regulating it, or what makes it come on.”
Bishopric and her team set out to answer that question by determining what usually keeps p300 shut off in the early stages of life. They found that levels of the two microRNAs, miRNA-142-3p and -5p, are present in high levels in mouse models during early embryogenesis, then are virtually undetectable at birth until about three months of age, when they rise again and become abundant.
“We discovered that these microRNAs always drop during growth of the heart and we believe that’s partly a direct effect of the rise of p300 and other aspects of the growth signal pathway,” she said. “Levels of p300 can rise because these microRNAs are no longer expressed, and stay turned off because p300 represses them. So something happens during stress that gives p300 the upper hand and allows it to repress its repressor.”
In the short term, Bishopric said, p300’s dominance is positive because rising p300 levels protect the myocytes from toxins released during stress, increasing their survival. And, as she and her research team showed, over-expressing the p300-inhibiting microRNAs during heart growth induces heart failure and massive cardiac myocyte death. Unfortunately, problems develop when the positive response to stress endures too long, as it does in many chronic disorders such as hypertension and aortic valve disease.
As the authors noted, understanding the natural pathways that inhibit hypertrophy is a key step to developing therapeutics that prevent imbalanced heart growth and dysfunction.
“Although not established as a direct cause of heart failure, hypertrophy is a frequent precursor and companion of disease- and age-related cardiac dysfunction,” they wrote. “A better understanding of the mechanism by which growth of the heart becomes dysfunctional is needed to improve treatment options for this highly prevalent disorder.”
In addition to Bishopric, other study authors include lead author Salil Sharma, Ph.D., who is now at the University of California, Los Angeles; Jing Liu, M.D., now at Stanford University; Jianqin Wei, M.D., research assistant professor of medicine; Huijun Yuan, Ph.D., a post-doctoral fellow at UM; and Taifang Zhang, Ph.D., senior research associate.