ABSTRACT
The present study investigated the effect of enalapril on myocardial infarction (MI) and its mechanism of action in mice. Treatment with enalapril significantly attenuated cellular apoptosis and death. In vivo, enalapril treatment alleviated MI injury, and decreased myocardial apoptosis and the size of the infarct area. This was paralleled by increased Bcl-2 expression, decreased Bax expression, a decreased caspase-3 level, decreased expression of endoplasmic reticulum stress-associated proteins, including activating transcription factor 6 and 78 kDa glucose-regulated protein, and fewer TUNEL-positive cells in the heart. Furthermore, enalapril-treatment increased transforming growth factor-activated kinase 1/nuclear factor of activated T cells 3 signaling, which protected the myocardium.
ABSTRACT
Long noncoding RNAs (lncRNAs) play important roles in the regulation of genes involved in cell proliferation. We have previously sought to more globally understand the differences of lncRNA expression between human fetal heart and adult heart to identify some functional lncRNAs which involve in the process of heart repair. We found that a highly conserved long noncoding RNA NR_045363 was mainly expressed in cardiomyocytes and rarely in non-cardiomyocytes. NR_045363 overexpression in 7-day-old mice heart could improve cardiac function and stimulate cardiomyocyte proliferation after myocardial infarction. Furthermore, NR_045363 knockdown inhibited proliferation of primary embryonic cardiomyocytes, while NR_045363 overexpression enhanced DNA synthesis and cytokinesis in neonatal cardiomyocytes in vitro. Mechanistic analysis revealed that NR_045363 promoted cardiomyocyte proliferation through interaction with miR-216a, which regulated the JAK2-STAT3 pathway. Our results showed that NR_045363 is a potent lncRNA modulator essential for cardiomyocyte proliferation.
Subject(s)
Myocardium/pathology , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , RNA, Long Noncoding/metabolism , Wound Healing , Animals , Animals, Newborn , Base Sequence , Cell Proliferation , Conserved Sequence , Heart/embryology , Humans , Janus Kinases/metabolism , Mice , MicroRNAs/metabolism , Myocardial Infarction/genetics , Myocardial Infarction/physiopathology , Regeneration , STAT3 Transcription Factor/metabolism , Signal TransductionABSTRACT
BACKGROUND/AIMS: Increasing evidence indicates that microRNAs (miRNAs) play important roles in Kawasaki disease (KD). Our previous study demonstrated that hsa-miR-27b-3p (miR-27b) was up-regulated in KD serum. However, the specific role of miR-27b in KD remains unclear. We aimed to investigate that miR-27b could be a biomarker and therapeutic target for KD treatment. As well, the specific mechanism of miR-27b effecting endothelial cell functions was studied. METHODS: The expression of miR-27b and Smad7 was measured by qRT-PCR. Gain-of-function strategy was used to observe the effect of miR-27b on human umbilical vein endothelial cells (HUVECs) proliferation and migration. Bioinformatics analyses were applied to predict miR-27b targets and then we verified Smad7 by a luciferase reporter assay. Western blot was performed to detect the protein expression of Smad7, PCNA, MMP9, MMP12 and TGF-ß-related genes. RESULTS: We confirmed that miR-27b was shown to be dramatically up-regulated in KD serum and KD serum-treated HUVECs and that elevated expression of miR-27b suppressed the proliferation and migration of HUVECs. Furthermore, our results verified that miR-27b mediated cell functions by affecting the TGF-ß via targeting Smad7 in HUVECs. CONCLUSION: These results suggested that up-regulated miR-27b had a protective role in HUVECs proliferation and migration via targeting Smad7 and affecting TGF-ß pathway. Therefore, miR-27b represented a potential biomarker for KD and may serve as a promising therapeutic target for KD treatment.
Subject(s)
MicroRNAs/metabolism , Mucocutaneous Lymph Node Syndrome/pathology , Smad7 Protein/metabolism , Antagomirs/metabolism , Area Under Curve , Case-Control Studies , Cell Movement , Cell Proliferation , Child , Child, Preschool , Female , Human Umbilical Vein Endothelial Cells , Humans , Infant , Male , MicroRNAs/antagonists & inhibitors , MicroRNAs/blood , Mucocutaneous Lymph Node Syndrome/metabolism , RNA Interference , RNA, Small Interfering/metabolism , ROC Curve , Signal Transduction , Smad7 Protein/antagonists & inhibitors , Smad7 Protein/genetics , Transforming Growth Factor beta/metabolismABSTRACT
Kawasaki disease (KD) is an acute, selflimited vasculitis that predominantly affects mediumsized arteries, particularly the coronary arteries. Recent studies have indicated that microRNAs are involved in many diseases, including KD. However, the detailed mechanism remains unclear. The aim of the present study was to explore the role of miR186 in KD and potentially discover a new target for KD treatment. The results demonstrated that miR186 was upregulated in serum from patients with KD and KD serum could increase miR186 transcript levels in endothelial cells (HUVECs). Overexpression of miR186 mimic induced HUVEC apoptosis through mitogenactivated protein kinase (MAPK) activation by targeting and inhibiting SMAD family member 6 (SMAD6). Furthermore, KD serum induced HUVEC apoptosis through miR186. In conclusion, the present results suggested that KD serumassociated miR186 has an essential role in endothelial cell apoptosis by activating the MAPK pathway through targeting the SMAD6 gene.
