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 conditions^{4, 5}. Other lncRNA molecules such as Ahit and Chaer have also been shown to play a role in hypertrophic response^{6, 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 injections^4-6. Small interfering RNA (siRNAs) were used to knockdown lncRNAs^{4, 5}. Transaortic Constriction (TAC) surgery was used to induce hypertrophic conditions in mice as well as pigs^{5, 6}. Phenylephrine was used to induce hypertrophic conditions in cell culture models^4-6. RNA immunoprecipitation assays were used to assess interactions between lncRNAs with whole cell lysate proteins^4-6. Various cell types were utilized in these studies including Neonatal Rat Ventricular Myocytes (NRVM), HL-1 cells^4-6. 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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5. Viereck J, Bührke A, Foinquinos A, et al. Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy. Eur Heart J. Sep 21 2020;41(36):3462-3474. doi:10.1093/eurheartj/ehaa519
6. Wang Z, Zhang XJ, Ji YX, et al. The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy. Nat Med. Oct 2016;22(10):1131-1139. doi:10.1038/nm.4179
7. Yu J, Yang Y, Xu Z, et al. Long Noncoding RNA Ahit Protects Against Cardiac Hypertrophy Through SUZ12 (Suppressor of Zeste 12 Protein Homolog)-Mediated Downregulation of MEF2A (Myocyte Enhancer Factor 2A). Circ Heart Fail. Jan 2020;13(1):e006525. doi:10.1161/circheartfailure.119.006525