Department of Medical Specialties-Endocrinology, Diabetology, Hypertension and Nutrition, University of Geneva, Geneva, Switzerland.
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, Genoa, Italy.
PLoS One. 2019 Jun 20;14(6):e0218432. doi: 10.1371/journal.pone.0218432. eCollection 2019.
High density lipoprotein (HDL) protects against myocardial infarction via mechanisms that remain unclear. STAT3 (signal transducer and activator of transcription 3) plays a key role in HDL-induced cardioprotection. In the heart, microRNAs (miRNAs) are involved in ischemia reperfusion injury. We therefore investigated whether the cardioprotective effect of HDL modulates miRNAs as a downstream target of STAT3 activation.
STAT3 cardiomyocyte deficient mice (STAT3-KO) and wildtype littermates (STAT3-WT) were submitted to left coronary ligature and reperfused (IR) with or without injection of HDL. Infarct size (IS) was determined and cardiac miRNA expression was evaluated after reperfusion in sham, IR and IR+HDL hearts by microarray analysis. In vitro, neonatal rat ventricular cardiomyocytes were submitted to hypoxia with or without HDL incubation. Cell viability and miRNA expression were analysed.
In vivo, HDL reduced IS from 40.5±4.3% to 24.4±2.1% (p<0.05) in STAT3-WT mice. HDL failed to protect in STAT3-KO mice. In STAT3-WT mice, both miR-34b and miR-337 were increased in IR compared to sham and IR+HDL groups (p<0.05). These miRNAs were not modulated in STAT3-KO mice. In vitro, incubation with HDL improved cell viability against hypoxia (p<0.05). The expression of miR-34b and miR-337 was increased by hypoxia and reduced by HDL treatment (p<0.05). In cardiomyocytes transfected with miRNA mimics, HDL failed to improve cell viability against hypoxia.
Our study, performed both in vivo and in vitro, delineates a novel cardioprotective signalling pathway activated by HDL, involving STAT3-mediated decrease of miR-34b and miR-337 expression.
高密度脂蛋白（HDL）通过尚不清楚的机制来预防心肌梗死。STAT3（信号转导和转录激活因子 3）在 HDL 诱导的心脏保护中起着关键作用。在心脏中，microRNAs（miRNAs）参与缺血再灌注损伤。因此，我们研究了 HDL 的心脏保护作用是否通过 STAT3 激活的下游靶标来调节 miRNAs。
STAT3 心肌细胞缺陷小鼠（STAT3-KO）和野生型同窝小鼠（STAT3-WT）接受左冠状动脉结扎并再灌注（IR），或在注射 HDL 前后接受再灌注。在 sham、IR 和 IR+HDL 心脏中，通过微阵列分析评估再灌注后梗死面积（IS）和心脏 miRNA 表达。在体外，新生大鼠心室心肌细胞接受缺氧处理，并或不与 HDL 孵育。分析细胞活力和 miRNA 表达。
体内，HDL 将 STAT3-WT 小鼠的 IS 从 40.5±4.3%降低至 24.4±2.1%（p<0.05）。HDL 在 STAT3-KO 小鼠中未能发挥保护作用。在 STAT3-WT 小鼠中，与 sham 和 IR+HDL 组相比，IR 导致 miR-34b 和 miR-337 表达增加（p<0.05）。这些 miRNA 在 STAT3-KO 小鼠中未被调节。在体外，与 HDL 孵育可改善缺氧条件下的细胞活力（p<0.05）。miR-34b 和 miR-337 的表达在缺氧条件下增加，而在 HDL 处理后减少（p<0.05）。在转染 miRNA 模拟物的心肌细胞中，HDL 未能改善缺氧条件下的细胞活力。
我们的研究在体内和体外均表明，HDL 激活了一条新的心脏保护信号通路，涉及 STAT3 介导的 miR-34b 和 miR-337 表达减少。
