Aging-Associated miR-217 Aggravates Atherosclerosis and Promotes Cardiovascular Dysfunction.
Aging-Associated miR-217 Aggravates Atherosclerosis and Promotes Cardiovascular Dysfunction.
复制标题
DOI：
10.1161/atvbaha.120.314333
复制
发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Ramiro AR
中科院分区：
文献类型：
--
作者：
de Yébenes VG;Briones AM;Martos-Folgado I;Mur SM;Oller J;Bilal F;González-Amor M;Méndez-Barbero N;Silla-Castro JC;Were F;Jiménez-Borreguero LJ;Sánchez-Cabo F;Bueno H;Salaices M;Redondo JM;Ramiro AR
补充数字内容可在文本中找到。microRNA是基因表达的主要调节因子，在几乎所有生物过程中发挥重要作用。miR-217与衰老和细胞衰老有关，但其在血管疾病中的作用尚不清楚。我们使用了一种诱导型内皮特异性基因敲入小鼠模型来研究miR-217在血管功能和动脉粥样硬化中的作用。miR-217减少NO的产生，促进内皮功能障碍，增加血压，并加剧促动脉粥样硬化apoE−/−小鼠的动脉粥样硬化。此外，内皮miR-217表达增加导致冠状动脉疾病的发展和改变左心室心脏功能，诱导舒张和收缩功能障碍。相反，在apoE−/−小鼠中抑制内源性血管miR-217可改善血管收缩力并减少动脉粥样硬化。转录组分析显示，miR-217调节内皮信号中枢并下调eNOS（内皮NO合酶）激活剂网络，包括VEGF（血管内皮生长因子）和apelin受体途径，导致eNOS表达减少。进一步的分析显示，人血浆miR-217是血管老化和心血管风险的生物标志物。我们的研究结果强调了miR-217抑制剂在衰老相关心血管疾病中的治疗潜力。
Supplemental Digital Content is available in the text. microRNAs are master regulators of gene expression with essential roles in virtually all biological processes. miR-217 has been associated with aging and cellular senescence, but its role in vascular disease is not understood. We have used an inducible endothelium-specific knock-in mouse model to address the role of miR-217 in vascular function and atherosclerosis. miR-217 reduced NO production and promoted endothelial dysfunction, increased blood pressure, and exacerbated atherosclerosis in proatherogenic apoE−/− mice. Moreover, increased endothelial miR-217 expression led to the development of coronary artery disease and altered left ventricular heart function, inducing diastolic and systolic dysfunction. Conversely, inhibition of endogenous vascular miR-217 in apoE−/− mice improved vascular contractility and diminished atherosclerosis. Transcriptome analysis revealed that miR-217 regulates an endothelial signaling hub and downregulates a network of eNOS (endothelial NO synthase) activators, including VEGF (vascular endothelial growth factor) and apelin receptor pathways, resulting in diminished eNOS expression. Further analysis revealed that human plasma miR-217 is a biomarker of vascular aging and cardiovascular risk. Our results highlight the therapeutic potential of miR-217 inhibitors in aging-related cardiovascular disease.