Abstract
The development of cardiovascular pathologies is partly attributed to epigenetic causes, including histone methylation, which appears to be an important marker in hearts that develop cardiac hypertrophy. Previous studies showed that the histone demethylase JMJD2A can regulate the hypertrophic process in murine cardiomyocytes. However, the influence of JMJD2A on cardiac hypertrophy in a human cardiomyocyte model is still poorly understood. In the present study, cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) were used. Hypertrophy was induced by angiotensin II and endothelin-1 (ET-1), and transfections were performed to overexpress JMJD2A and for small interfering RNA (siRNA)-induced silencing of JMJD2A. Gene expression analyses were determined using RT-PCR and Western blot. The expression levels of B-type natriuretic peptide (BNP), natriuretic peptide A (ANP), and beta myosin heavy chain (β-MHC) were increased by nearly 2–10-fold with ET-1 compared with the control. However, a higher level of JMJD2A and UTX was detected, whereas the level of JMJD2C was lower. When cardiomyocytes were transiently transfected with JMJD2A, an increase close to 150% in BNP was observed, and this increase was greater after treatment with ET-1. To verify the specificity of JMJD2A activity, a knockdown was performed by means of siRNA-JMJD2A, which led to a significant reduction in BNP. The involvement of JMJD2A suggests that histone-specific modifications are associated with genes encoding proteins that are actively transcribed during the hypertrophy process. Since BNP is closely related to JMJD2A expression, we suggest that there could be a direct influence of JMJD2A on the expression of BNP. These results may be studied further to reduce cardiac hypertrophy via the regulation of epigenetic modifiers.
Highlights
At the molecular level, post-translational modifications in histones play an important role in the regulation of gene expression, and they are part of the epigenetic memory system that regulates cell fate and functional specificity (Gurard-Levin and Almouzni, 2014)
Angiotensin II (Ang II) and endothelin-1 (ET-1) have been established for a model to promote hypertrophy; the underlying mechanism is related to the induction of several signaling cascades, which include an increase in intracellular calcium Ca2+ through the activation of calcium/calmodulindependent protein kinase II (CaMKII) or calcineurin, which is an end that mediates cardiac growth (Bupha-Intr et al, 2012)
For the robustness of the technology using cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs), sarcomeric organization was not thoroughly investigated
Summary
Post-translational modifications in histones play an important role in the regulation of gene expression, and they are part of the epigenetic memory system that regulates cell fate and functional specificity (Gurard-Levin and Almouzni, 2014). Cardiac hypertrophy is triggered by mechanic-transduction effects and by neurohormonal effects (Shimizu and Minamino, 2016). Most models of cardiac hypertrophy (deAlmeida et al, 2010) have been realized through mechanical effects through transverse aortic constriction (TAC) (Zhang et al, 2011), and relatively few studies have evaluated neurohormonal activity in the pathogenesis of cardiac hypertrophy (Shimizu and Minamino, 2016). Angiotensin II (Ang II) and endothelin-1 (ET-1) have been established for a model to promote hypertrophy; the underlying mechanism is related to the induction of several signaling cascades, which include an increase in intracellular calcium Ca2+ through the activation of calcium/calmodulindependent protein kinase II (CaMKII) or calcineurin, which is an end that mediates cardiac growth (Bupha-Intr et al, 2012)
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