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LPS induces HUVEC angiogenesis in vitro through miR-146a-mediated TGF-?1 inhibition.

ABSTRACT: Angiogenesis is an essential process for tissue growth and embryo development. However, inflammation, abnormal wound healing, vascular diseases, and tumor development and progression can result from inappropriate angiogenesis. Lipopolysaccharide (LPS) can activate various cells and alter endothelium function and angiogenesis. This study investigated the underlying molecular events involved in LPS-induced angiogenesis and revealed a novel strategy for controlling abnormal angiogenesis. LPS treatment promoted wound healing and tube formation in human umbilical vein endothelial cell (HUVEC) cultures and induced their expression of miR-146a. miR-146a was previously shown to regulate angiogenesis in HUVECs. Knockdown of miR-146a expression antagonized LPS-induced angiogenesis in vitro. Moreover, bioinformatic analyses predicted TGF-?1 as a target gene for miR-146a, which was confirmed by aluciferase reporter assay. Expression of miR-146a in HUVECs resulted in downregulation of TGF-?1 in HUVECs, whereas a miR-146a inhibitor upregulated the expression of TGF-?1 and TGF-?1 downstream proteins, such as phosphoraylation-Smad2 and plasminogen activator inhibitor type 1 (PAI-1). Furthermore, the TGF-?1 signaling inhibitor SB431542 impaired the ability of miR-146a knockdown to suppress LPS-induced angiogenesis. Thus, LPS-induced angiogenesis of HUVECs functions through miR-146a upregulation and TGF-?1 inhibition. This study suggests that knockdown of miR-146a could activate TGF-?1 signaling to inhibit angiogenesis as a potential therapy for angiogenesis-related diseases.

SUBMITTER: Li Y

PROVIDER: S-EPMC5340693 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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LPS induces HUVEC angiogenesis <i>in vitro</i> through miR-146a-mediated TGF-β1 inhibition.

Li Yize Y Zhu Huayu H Wei Xu X Li Heng H Yu Zhicao Z Zhang Hongmei H Liu Wenchao W

American journal of translational research 20170215 2

Angiogenesis is an essential process for tissue growth and embryo development. However, inflammation, abnormal wound healing, vascular diseases, and tumor development and progression can result from inappropriate angiogenesis. Lipopolysaccharide (LPS) can activate various cells and alter endothelium function and angiogenesis. This study investigated the underlying molecular events involved in LPS-induced angiogenesis and revealed a novel strategy for controlling abnormal angiogenesis. LPS treatm ...[more]

PMID: 28337286

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Project description:RATIONALE:Abnormal SUMOylation has emerged as a characteristic of heart failure (HF) pathology. Previously, we found reduced SUMO1 (small ubiquitin-like modifier 1) expression and SERCA2a (sarcoplasmic reticulum Ca2+-ATPase) SUMOylation in human and animal HF models. SUMO1 gene delivery or small molecule activation of SUMOylation restored SERCA2a SUMOylation and cardiac function in HF models. Despite the critical role of SUMO1 in HF, the regulatory mechanisms underlying SUMO1 expression are largely unknown. OBJECTIVE:To examine miR-146a-mediated SUMO1 regulation and its consequent effects on cardiac morphology and function. METHODS AND RESULTS:In this study, miR-146a was identified as a SUMO1-targeting microRNA in the heart. A strong correlation was observed between miR-146a and SUMO1 expression in failing mouse and human hearts. miR-146a was manipulated in cardiomyocytes through AAV9 (adeno-associated virus serotype 9)-mediated gene delivery, and cardiac morphology and function were analyzed by echocardiography and hemodynamics. Overexpression of miR-146a reduced SUMO1 expression, SERCA2a SUMOylation, and cardiac contractility in vitro and in vivo. The effects of miR-146a inhibition on HF pathophysiology were examined by transducing a tough decoy of miR-146a into mice subjected to transverse aortic constriction. miR-146a inhibition improved cardiac contractile function and normalized SUMO1 expression. The regulatory mechanisms of miR-146a upregulation were elucidated by examining the major miR-146a-producing cell types and transfer mechanisms. Notably, transdifferentiation of fibroblasts triggered miR-146a overexpression and secretion through extracellular vesicles, and the extracellular vesicle-associated miR-146a transfer was identified as the causative mechanism of miR-146a upregulation in failing cardiomyocytes. Finally, extracellular vesicles isolated from failing hearts were shown to contain high levels of miR-146a and exerted negative effects on the SUMO1/SERCA2a signaling axis and hence cardiomyocyte contractility. CONCLUSIONS:Taken together, our results show that miR-146a is a novel regulator of the SUMOylation machinery in the heart, which can be targeted for therapeutic intervention.

Dataset Information

LPS induces HUVEC angiogenesis in vitro through miR-146a-mediated TGF-?1 inhibition.

Publications

LPS induces HUVEC angiogenesis <i>in vitro</i> through miR-146a-mediated TGF-β1 inhibition.

Similar Datasets

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