Isoprenaline Inhibits Histone Demethylase LSD1 to Induce Cardiac Hypertrophy

Histone demethylation in cardiac hypertrophy is poorly understood. This study aims to determine the role of the histone demethylase LSD1 in pathological cardiac hypertrophy. Both isoprenaline (ISO)-treated and transverse aortic constriction (TAC)-treated rats developed hypertrophic hearts. LSD1 was significantly decreased; the histone marks mono- and dimethyl H3K4 and H3K9 (H3K4me1/2 and H3K9me1/2) were significantly up-regulated in the hypertrophic heart tissue, as well as the expression of the ANP, alpha-HMC and MLV-2v genes. An LSD1 inhibitor, OG-L002 could also induce cardiac hypertrophy and enhance the induction of cardiac hypertrophy by ISO. Overexpressed LSD1 abolished ISO-induced cardiac hypertrophy and downregulated H3K4me1/2 and H3K9me1/2 expression. Overexpression of LSD1 also reduced the expression of ANP, alpha-HMC and MLV-2v. In addition, we have reported isoprenaline (ISO) as one of the histone demethylase LSD1 inhibitors. This was confirmed by molecular docking, molecular dynamic studies and a histone demethylation assay. The H3K4me1/2 expression increases with the incubation of ISO in HEK 293T and HELA cells. CaMKII could be significantly activated by the LSD1 inhibitor OG-L002 as well as by ISO in rats. In summary, we have identified a novel role for LSD1 in initiating and maintaining cardiac hypertrophy.