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In the presence of conditions such as high blood pressure and reduced blood flow to the heart muscle, the heart of the adult can significantly get fat, a process called pathological hypertrophy that preserves short-term heart function term but predisposes patients to persistent heart failure and sudden death of untreated cardiac Researchers at the University of North Carolina's Faculty of Medicine discovered that the Lin28a RNA binding protein was necessary for the development of pathological hypertrophy.
Posted in the journal circulation, the discovery could have a significant impact on the development of more powerful treatments for the treatment of heart disease, the leading cause of death in the United States and around the world.
"One of the first steps in gene regulation is the transcription of a DNA sequence into RNA. However, post-transcriptional regulation by RNA binding proteins is has become a critical regulatory layer for the control of gene function in health and disease, "said Jiandong Liu, PhD, badociate professor of pathology and laboratory medicine at the UNC and senior author of the ;study. During pathological hypertrophy, the heart undergoes important structural changes known to cause profound alterations in the expression of heart genes.
"The identification of Lin28a as a new regulator of pathological cardiac hypertrophy adds to the post-transcriptional regulation of RNA a new mechanism underlying this important actor of heart disease", added Liu.
One of the main features of cardiac hypertrophy is a change in metabolism because the hypertrophic heart relies more on glucose metabolism – when glucose is turned into energy for cells – than the oxidation of fatty acids, different process used by the cells to create energy.
"It is interesting to note that most of the genes regulated by Lin28a at the beginning of cardiac hypertrophy are enriched in metabolism and metabolism-related cell pathways, and that Lin28a helps to increase glycolysis and decrease blood glucose levels. oxidation of fatty acids in hypertrophic hearts, "said Liu. is also a member of the McAllister Heart Institute of UNC-Chapel Hill.
Using various research techniques, including new generation sequencing, RNA immunoprecipitation and gene expression badysis, the Liu research group has also identified part of the mechanism by which Lin28a stimulates hypertrophy. His laboratory discovered that Lin28a targets the Pck2 gene, which encodes a mitochondrial protein essential to the heart to improve glycolysis.
"Our study provides strong evidence that Lin28a plays an important role in the response to cardiac stress during pathological hypertrophy," Liu said. "By binding directly to Pck2 mRNA, Lin28a facilitates an important switch in the metabolism treatment needed for the heart to expand in response to stress." These findings are consistent with those from previous studies that also showed that a metabolic shift was to occur before the heart could dilate drastically.
Overall, Liu's results support the idea that a change in metabolic treatment during the early stages of cardiac hypertrophy may be critical for restructuring and enlarging the heart in response to cardiac stress.
"The identification of key genes such as Lin28a and Pck2 that facilitate this switching of cardiac metabolism, and which ultimately lead to hypertrophy of the heart, is a major step in the creation of potential therapeutic options for those who are suffering of pathological hypertrophy and heart failure, "said Liu. .
The co-authors of the study include Hong Ma, Shuo Yu, Zhang Yingao, Thomas Fakadej, Liu Ziqing, Chaoying Yin, Joan M. Taylor and Li Qian of the University of North Carolina at Chapel Hill, Xiaojing Liu and Jason W. Locasale of Duke. University and Weining Shen of the University of California at Irvine, Irvine.
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