The Role of H19 and Other Long Non-Coding RNAs in Cardiac Hypertrophy: Novel Treatment and Prevention Strategies for Hypertrophic Cardiomyopathy
Matthew Wooten
Purpose. Hypertrophic Cardiomyopathy (HCM) is characterized by abnormal hypertrophy of the heart, often with preference of the interventricular septum.1, 2 It’s prevalence is as high as 1 in 500 adults, and is the most common cause of sudden cardiac death in young athletes.1 It is typically caused by mutations in many sarcomeric proteins, but has also been linked most recently to mutations in H19, a long non-coding RNA (lncRNA)3. Other studies have shown that H19 likely has an anti-hypertrophic role in cardiac remodeling in pro-hypertrophic conditions4, 5. Other lncRNA molecules such as Ahit and Chaer have also been shown to play a role in hypertrophic response6, 7. All three have been found to interact with the epigenetic remodeler Polycomb Repressive Complexes 2 (PRC2)5-7. These molecules and their partner interactions could hold the key to reversal of hypertrophy for HCM patients. Methods. Adenoviruses were used to overexpress RNAs in murine models, through tail injections4-6. Small interfering RNA (siRNAs) were used to knockdown lncRNAs4, 5. Transaortic Constriction (TAC) surgery was used to induce hypertrophic conditions in mice as well as pigs5, 6. Phenylephrine was used to induce hypertrophic conditions in cell culture models4-6. RNA immunoprecipitation assays were used to assess interactions between lncRNAs with whole cell lysate proteins4-6. Various cell types were utilized in these studies including Neonatal Rat Ventricular Myocytes (NRVM), HL-1 cells4-6. Results. Ahit was shown to be more highly expressed in hypertrophic state, and localized to the nucleus.7 Ahit was also shown to bind to PRC2.7 Chaer knock-down led to decreased cells size in hypertrophic states, while overexpression led to a notable increase.6 Chaer was also shown to be involved with trimethylation of H3K27, through binding of PRC2.6 It also led to expression of H19.6 H19 overexpression led to a reduced cell size, while knockdown led to increases in cell size.4 H19 was found to interact with PRC2 through multiple subunits, leading to increased expression of Tescalcin, a negative modulator of the pro-hypertrophic signaling molecule NFAT.5 When introduced via Adenovirus tail injection, both murine and human H19 reversed hypertrophy in murine models, while preserving cardiac function5. H19 alleles were also shown to correlate with HCM in human patients when known gene mutations were excluded3. Conclusion. lncRNAs, especially H19, play an important role in cardiac hypertrophy. Modulating H19 could provide a possible avenue for treatments of not just HCM, but any condition characterized by abnormal hypertrophy of the heart.
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