Epigenetic regulations essentially participate in the development of cardiomyocyte hypertrophy. PHD finger protein 19 (PHF19) is a polycomb protein that controls H3K36me3 and H3K27me3. However, the roles of PHF19 in cardiac hypertrophy remain unknown. Here in this work, we observed that PHF19 promoted cardiac hypertrophy via epigenetically targeting SIRT2. In angiotensin II (Ang II)-induced cardiomyocyte hypertrophy, adenovirus-mediated knockdown of Phf19 reduced the increase in cardiomyocyte size, repressed the expression of hypertrophic marker genes Anp and Bnp, as well as inhibited protein synthesis. By contrast, Phf19 overexpression promoted Ang II-induced cardiomyocyte hypertrophy in vitro. We also knocked down Phf19 expression in mouse hearts in vivo. The results demonstrated that Phf19 knockdown reduced Ang II-induced decline in cardiac fraction shortening and ejection fraction. Phf19 knockdown also inhibited Ang II-mediated increase in heart weight, reduced cardiomyocyte size, and repressed the expression of hypertrophic marker genes in mouse hearts. Further mechanism studies showed that PHF19 suppressed the expression of SIRT2, which contributed to the function of PHF19 during cardiomyocyte hypertrophy. PHF19 bound the promoter of SIRT2 and regulated the balance between H3K27me3 and H3K36me3 to repress the expression of SIRT2 in vitro and in vivo. In human hypertrophic hearts, the overexpression of PHF19 and downregulation of SIRT2 were observed. Of importance, PHF19 expression was positively correlated with hypertrophic marker genes ANP and BNP but negatively correlated with SIRT2 in human hypertrophic hearts. Therefore, our findings demonstrated that PHF19 promoted the development of cardiac hypertrophy via epigenetically regulating SIRT2.

表观遗传调控本质上参与了心肌细胞肥大的发展。PHD 指蛋白 19 (PHF19) 是一种多梳蛋白，可控制 H3K36me3 和 H3K27me3。然而，PHF19 在心脏肥大中的作用仍然未知。在这项工作中，我们观察到 PHF19 通过表观遗传靶向 SIRT2 促进心脏肥大。在血管紧张素 II (Ang II) 诱导的心肌细胞肥大中，腺病毒介导的Phf19敲低减少了心肌细胞大小的增加，抑制了肥大标记基因Anp和Bnp的表达，并抑制了蛋白质合成。相比之下，Phf19过表达在体外促进了 Ang II 诱导的心肌细胞肥大。我们也打倒了Phf19在体内小鼠心脏中的表达。结果表明，Phf19敲低降低了 Ang II 诱导的心脏分数缩短和射血分数的下降。Phf19敲低还抑制了 Ang II 介导的心脏重量增加，减小了心肌细胞的大小，并抑制了小鼠心脏中肥大标记基因的表达。进一步的机制研究表明，PHF19 抑制 SIRT2 的表达，这有助于 PHF19 在心肌细胞肥大过程中的功能。PHF19 结合 SIRT2 的启动子并调节 H3K27me3 和 H3K36me3 之间的平衡，从而在体外和体内抑制 SIRT2 的表达。在人类肥大心脏中，观察到 PHF19 的过表达和 SIRT2 的下调。重要的是，在人类肥大心脏中，PHF19的表达与肥大标记基因ANP和BNP呈正相关，但与SIRT2呈负相关。因此，我们的研究结果表明，PHF19 通过表观遗传调控 SIRT2 促进了心脏肥大的发展。