The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, PR China.
Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
J Hypertens. 2018 Sep;36(9):1847-1857. doi: 10.1097/HJH.0000000000001769.
PDE5A is a leading factor contributing to cGMP signaling and cardiac hypertrophy. However, microRNA-mediated posttranscriptional regulation of PDE5A has not been reported. The aim of this study is to screen the microRNAs that are able to regulate PDE5A and explore the function of the microRNAs in cardiac hypertrophy and remodeling.
Although miR-19a/b-3p (microRNA-19a-3p and microRNA-19b-3p) have been reported to be differentially expressed during cardiac hypertrophy, the direct targets and the functions of this microRNA family for regulation of cardiac hypertrophy have not yet been investigated. The present study identified some direct targets and the underlying functions of miR-19a/b-3p by using bioinformatics tools and gene manipulations within mouse neonatal cardiomyocytes. Transfection of miR-19a/b-3p down-regulated endogenous expressions of PDE5A at both mRNA and protein levels with real-time PCR and western blot. Luciferase reporter assays showed that PDE5A was a direct target of miR-19a/b-3p. In mouse models of cardiac hypertrophy, we found that miR-19a/b-3p was expressed in cardiomyocytes and that its expression was reduced in pressure overload-induced hypertrophic hearts. miR-19a/b-3p transgenic mice prevented the progress of cardiac hypertrophy and cardiac remodeling in response to angiotensin II infusion with echocardiographic assessment and pressure-volume relation analysis.
Our study elucidates that PDE5A is a novel direct target of miR-19a/b-3p, and demonstrates that antihypertrophic roles of the miR-19a/b-3p family in Ang II-induced hypertrophy and cardiac remodeling, suggests that endogenous miR-19a/b-3p might have clinical potential to suppress cardiac hypertrophy and heart failure.
PDE5A 是 cGMP 信号转导和心肌肥厚的主要因素。然而，PDE5A 的 miRNA 介导的转录后调控尚未报道。本研究旨在筛选能够调节 PDE5A 的 microRNA，并探讨这些 microRNA 在心肌肥厚和重构中的功能。
虽然 miR-19a/b-3p（microRNA-19a-3p 和 microRNA-19b-3p）在心肌肥厚过程中已有报道，但该 microRNA 家族对心肌肥厚的直接靶点和功能尚未被研究。本研究通过使用生物信息学工具和在小鼠乳鼠心肌细胞中的基因操作，鉴定了一些 miR-19a/b-3p 的直接靶点及其潜在功能。miR-19a/b-3p 的转染可在实时 PCR 和 Western blot 中下调内源性 PDE5A 的 mRNA 和蛋白表达。荧光素酶报告基因实验表明 PDE5A 是 miR-19a/b-3p 的直接靶点。在心肌肥厚的小鼠模型中，我们发现 miR-19a/b-3p 在心肌细胞中表达，在压力超负荷诱导的肥厚心脏中表达减少。miR-19a/b-3p 转基因小鼠通过超声心动图评估和压力-容积关系分析，在血管紧张素 II 输注时预防了心肌肥厚和心脏重构的进展。
本研究阐明了 PDE5A 是 miR-19a/b-3p 的一个新的直接靶点，并证明了 miR-19a/b-3p 家族在 Ang II 诱导的肥厚和心脏重构中的抗肥厚作用，提示内源性 miR-19a/b-3p 可能具有抑制心肌肥厚和心力衰竭的临床潜力。
