Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China.
J Cell Physiol. 2019 Aug;234(8):13169-13181. doi: 10.1002/jcp.27987. Epub 2019 Jan 21.
Heart failure (HF) is a disease with high mortality and morbidity rate. Previous studies have shown that microRNAs (miRNAs) may be implicated in the pathogenesis of HF, potentially being able to improve the cardiac function in an HF rat model. The present study was designed to define the role of miR-665 in the cardiac function of the HF rats. Following the establishm;ent of the rat models of HF, the functional role miR-665 in HF was determined using an ectopic expression and knockdown experiments. The cardiac function was evaluated with the determination of ventricular mass index and hemodynamic parameters. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining was performed, with the apoptosis of cardiac cells detected in the process. The expression of miR-665, glucagon-like peptide 1 receptor (GLP1R), cyclic adenosine monophosphate (cAMP) signaling pathway-related, and apoptosis-related genes was examined. Enzyme-linked immunosorbent assay was conducted to determine the levels of inflammation-related genes. Initially, the upregulation of miR-665, downregulation of GLP1R, and inactivation of cAMP signaling pathway were observed in HF rats. GLP1R was a target of miR-665. Forced expression of miR-665 promoted cell apoptosis and inhibited GLP1R and the cAMP signaling pathway. In addition, miR-665 overexpression has been known to impair cardiac function, promote inflammatory response while elevating malondialdehyde and superoxide dismutase levels, and decreasing mitochondrial respiratory chain enzyme activities. Furthermore, we also observed that the effects of miR-665 inhibition had been reversed when the cAMP signaling pathway was also inhibited. This study demonstrates that miR-665 inhibition can stabilize the cardiac function of HF rats via the cAMP signaling pathway via upregulation of the GLP1R.
心力衰竭（HF）是一种死亡率和发病率都很高的疾病。先前的研究表明，微小 RNA（miRNA）可能与 HF 的发病机制有关，有可能改善 HF 大鼠模型中的心脏功能。本研究旨在确定 miR-665 在 HF 大鼠心脏功能中的作用。在建立 HF 大鼠模型后，通过异位表达和敲低实验确定了 miR-665 在 HF 中的功能作用。通过测定心室质量指数和血液动力学参数来评估心脏功能。进行末端脱氧核苷酸转移酶 dUTP 缺口末端标记染色，检测心脏细胞的凋亡情况。检测 miR-665、胰高血糖素样肽 1 受体（GLP1R）、环磷酸腺苷（cAMP）信号通路相关和凋亡相关基因的表达。通过酶联免疫吸附试验测定炎症相关基因的水平。最初，在 HF 大鼠中观察到 miR-665 的上调、GLP1R 的下调和 cAMP 信号通路的失活。GLP1R 是 miR-665 的靶标。强制表达 miR-665 促进细胞凋亡，抑制 GLP1R 和 cAMP 信号通路。此外，已知 miR-665 的过表达会损害心脏功能，促进炎症反应，同时提高丙二醛和超氧化物歧化酶水平，并降低线粒体呼吸链酶活性。此外，我们还观察到当 cAMP 信号通路也被抑制时，miR-665 抑制的作用被逆转。本研究表明，miR-665 抑制可通过上调 GLP1R 通过 cAMP 信号通路稳定 HF 大鼠的心脏功能。
