Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Gender in Medicine and Center for Cardiovascular Research, and DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany.
Biol Sex Differ. 2019 Feb 6;10(1):8. doi: 10.1186/s13293-019-0222-1.
Maladaptive remodeling in pressure overload (PO)-induced left ventricular hypertrophy (LVH) may lead to heart failure. Major sex differences have been reported in this process. The steroid hormone 17β-estradiol, along with its receptors ERα and ERβ, is thought to be crucial for sex differences and is expected to be protective, but this may not hold true for males. Increasing evidence demonstrates a major role for microRNAs (miRNAs) in PO-induced LVH. However, little is known about the effects of biological sex and ERβ on cardiac miRNA regulation and downstream mitochondrial targets. We aimed at the analysis of proteins involved in mitochondrial metabolism testing the hypothesis that they are the target of sex-specific miRNA regulation.
We employed the transverse aortic constriction model in mice and assessed the levels of five mitochondrial proteins, i.e., Auh, Crat, Decr1, Hadha, and Ndufs4.
We found a significant decrease of the mitochondrial proteins primarily in the male overloaded heart compared with the corresponding control group. Following computational analysis to identify miRNAs putatively targeting these proteins, our in vitro experiments employing miRNA mimics demonstrated the presence of functional target sites for miRNAs in the 3'-untranslated region of the messenger RNAs coding for these proteins. Next, we assessed the levels of the functionally validated miRNAs under PO and found that their expression was induced only in the male overloaded heart. In contrast, there was no significant effect on miRNA expression in male mice with deficient ERβ.
We put forward that the male-specific induction of miRNAs and corresponding downregulation of downstream protein targets involved in mitochondrial metabolism may contribute to sex-specific remodeling in PO-induced LVH.
在压力超负荷（PO）引起的左心室肥厚（LVH）中，适应性重构可能导致心力衰竭。在这个过程中，已经报道了主要的性别差异。甾体激素 17β-雌二醇及其受体 ERα 和 ERβ 被认为对性别差异至关重要，并且预计具有保护作用，但这在男性中可能并不成立。越来越多的证据表明 microRNAs（miRNAs）在 PO 诱导的 LVH 中起主要作用。然而，对于生物性别和 ERβ 对心脏 miRNA 调节和下游线粒体靶标的影响知之甚少。我们旨在分析参与线粒体代谢的蛋白质，检验它们是性别特异性 miRNA 调节的靶标的假设。
我们采用了小鼠的主动脉缩窄模型，并评估了五种线粒体蛋白的水平，即 Auh、Crat、Decr1、Hadha 和 Ndufs4。
我们发现，与相应的对照组相比，雄性超负荷心脏中的这些线粒体蛋白水平显著降低。在进行计算分析以鉴定可能靶向这些蛋白质的 miRNA 后，我们的体外实验使用 miRNA 模拟物表明，这些蛋白质的信使 RNA 的 3'-非翻译区存在 miRNA 的功能靶位。接下来，我们评估了 PO 下这些功能验证的 miRNA 的水平，发现它们的表达仅在雄性超负荷心脏中被诱导。相比之下，在缺乏 ERβ 的雄性小鼠中，miRNA 表达没有显著影响。
我们提出，miRNA 的雄性特异性诱导及其下游参与线粒体代谢的蛋白质靶标的相应下调可能有助于 PO 诱导的 LVH 中的性别特异性重构。
