Led by senior author Nanette H. Bishopric, M.D., professor of medicine, pediatrics and pharmacology and Director of the UM Cardiovascular Genomics Laboratory, the study, “MicroRNA-20a constrains p300-driven myocardial angiogenic transcription by direct targeting of p300,” identifies the microRNA miR-20a as a natural mechanism that specifically targets and inhibits expression of p300 acetyltransferase, a nodal regulator of the cardiac hypertrophic response.
Working in Bishopric’s lab, co-first authors Lina A. Shehadeh, Ph.D., assistant professor of medicine, and Salil Sharma, Ph.D., a UM doctoral graduate who is now a postdoctoral fellow at the University of California Los Angeles David Geffen School of Medicine, determined the critical downstream effectors of p300 by observing transgenic mice engineered to overexpress the gene in the heart.
Under normal conditions, stress induces a short-term expression of p300, which protects cardiac myocytes from oxidative damage and apoptosis. But when stress is ongoing, the continuous expression of p300 can lead to heart failure and death. In their mouse models, the researchers noticed that overexpression of p300 prompted robust blood vessel growth together with increased angiogenic gene expression.
It was through this observation that Bishopric and her team, who just last year discovered two other p300-inhibiting microRNAs, found that a third microRNA, miR-20a, represses not only p300, but also the genes that regulate blood vessel formation. These observations point to miR-20a as an important negative regulator of angiogenesis in the heart.
“We have established p300 and miR-20a as a pair of antagonists whose balance determines the efficiency of blood vessel growth in the heart during stress,” Bishopric said. “In our study of p300, we found that it plays a central role in determining the extent of cardiac hypertrophy, a very common precursor to heart failure and death. Understanding how these microRNAs provide important regulatory control over the hypertrophic process may lead to new therapies for patients at risk for heart failure.”
In addition to Bishopric, Shehadeh and Sharma, other study authors include Mônica Pessanha, Ph.D., a UM postdoctoral fellow at the time of the study who is now Director of the Research-Stereology Division at Myofrastand Inc., Jian Qin Wei, M.D., research assistant professor of medicine, Jing Liu, M.D., a UM postdoctoral graduate now at Stanford University, Huijun Yuan, M.D., Ph.D., assistant scientist in the Department of Molecular and Cellular Pharmacology, Claudia O. Rodrigues, Ph.D., M.S., research assistant professor of molecular and cellular pharmacology, Michaela Scherr, from Hannover Medical School in Germany, and Nicholas F. Tsinoremas, Ph.D., professor of medicine, computer science and health informatics and Director of the Center for Computational Sciences.
University of Miami