Methylation‐dependent transcriptional repression of RUNX3 by KCNQ1OT1 regulates mouse cardiac microvascular endothelial cell viability and inflammatory response following myocardial infarction

• Published in: The FASEB journal Vol. 33; no. 12; pp. 13145 - 13160
• Main Authors: Wang, Yanbin, Yang, Xudong, Jiang, An, Wang, Wei, Li, Jian, Wen, Junmin
• Format: Journal Article
• Language: English
• Published: Bethesda, MD, USA Federation of American Societies for Experimental Biology 01-12-2019
• Subjects: Animals; Cell Survival - genetics; Cell Survival - physiology; Chromatin Immunoprecipitation; CMECs; Core Binding Factor Alpha 3 Subunit - genetics; Core Binding Factor Alpha 3 Subunit - metabolism; DNA (Cytosine-5-)-Methyltransferase 1 - genetics; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism; DNMT1; Immunoprecipitation; In Situ Nick-End Labeling; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction - genetics; Myocardial Infarction - immunology; Myocardial Infarction - metabolism; Potassium Channels, Voltage-Gated - genetics; Potassium Channels, Voltage-Gated - metabolism; MI; DNMT1; CMECs
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201900310R

Myocardial infarction (MI) is a major contributor to death and disability throughout the world. Increasing evidence shows that long noncoding RNAs (lncRNAs) are involved in the progression of MI. Here, we hypothesized that lncRNA potassium voltage‐gated channel subfamily q member 1 overlapping transcript 1 (KCNQ1OT1) could affect the development of MI via regulation of Runt‐related transcription factor (RUNX)3 by methylation. Initially, by ligation of the left anterior descending coronary artery, an acute MI (AMI) mouse model was established to collect the cardiac microvascular endothelial cells (CMECs), which revealed a high KCNQ1OT1 expression and a low RUNX3 expression with its high methylation. After that, KCNQ1OT1 knockdown or RUNX3 overexpression were transduced into the CMECs in order to detect their role in CMEC proliferation, apoptosis, and inflammatory response. Moreover, we assessed their interaction with the inflammatory Notch pathway, by determining the expression of Jagged 1, Hey1, Hes1, Notch intracellular domain, and Notch1. It was observed that after KCNQ1OT1 knockdown, the proliferation of AMI‐CMECs was promoted, whereas their apoptosis was inhibited, accompanied by reduced level of inflammatory factors. These trends could also be achieved by RUNX3 overexpression via the Notch pathway. Finally, the regulation of DNA methyltransferase (DNMT)1‐dependent methylation in RUNX3 by KCNQ1OT1 was determined, suggesting that KCNQ1OT1 could result in down‐regulated RUNX3 expression through promoted RUNX3 methylation caused by recruiting DNMT1. Overall, this study demonstrates that KCNQ1OT1 silencing inhibits RUNX3 methylation, thereby offering protection against CMEC injury and inflammatory response in AMI, which may serve as a promising target for the disease treatment.—Wang Y., Yang X., Jiang A., Wang W., Li, J., Wen, J. Methylation‐dependent transcriptional repression of RUNX3 by KCNQ1OT1 regulates mouse cardiac microvascular endothelial cell viability and inflammatory response following myocardial infarction. FASEB J. 33, 13145–13160 (2019). www.fasebj.org