Fig. 2 |. lncRNAs regulation of cardiac hypertrophy induced by calcium and NFAT.

a, Calcium is a key mediator of cardiac hypertrophy. Calcium enters the cell via calcium channels and is sequestered into the sarcoplasmic reticulum via the sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2). The long non-coding RNA (lncRNA) ZFAS1 (ZNFX1 antisense RNA 1) binds to and limits the activity of SERCA2 protein, resulting in elevated intracellular calcium levels. In the presence of calcium, calcineurin dephosphorylates nuclear factor of activated T cells (NFAT), which translocates to the nucleus and activates the transcription of prohypertrophic genes, including the lncRNA ZFAS1. b, The lncRNA HOTAIR (HOX antisense intergenic RNA) is proposed to alter calcium homeostasis by decreasing Ca²⁺ channel activity. Another lncRNA, H19, binds to the protein polycomb repressive complex 2 (PRC2) and thereby promotes the transcription of the TESC gene encoding tescalcin (TESC). The TESC protein inhibits the phosphorylation of glycogen synthase kinase 3 (GSK3), thereby enabling GSK3 to phosphorylate and prevent the DNA-binding function of NFAT. Similarly, TESC suppresses the phosphatase activity of calcineurin A¹⁹⁹. This pathway results in suppression of the hypertrophic gene response initiated by NFAT activation. Me, methyl group; P, phosphase group; Pol II, RNA polymerase II; SAM, S-adenosyl methionine.