Abstract
Myocardial ischaemia (MI) remains a major cause of death and disability worldwide. Accumulating evidence suggests a significant role for innate immunity, in which the family of toll‐like receptors (TLRs) acts as an essential player. We previously reported and reviewed the changes of Tlr expression in models of MI. However, the underlying mechanisms regulating Tlr expression in MI remain unclear. The present study first screened transcription factors (TFs) that potentially regulate Tlr gene transcription based on in silico analyses followed by experimental verification, using both in vivo and in vitro models. Forkhead box C1 (FOXC1) was identified as a putative TF, which was highly responsive to MI. Next, by focusing on two representative TLR subtypes, an intracellular subtype TLR3 and a cell‐surface subtype TLR4, the regulation of FOXC1 on Tlr expression was investigated. The overexpression or knockdown of FoxC1 was observed to up‐ or down‐regulate Tlr3/4 mRNA and protein levels, respectively. A dual‐luciferase assay showed that FOXC1 trans‐activated Tlr3/4 promoter, and a ChIP assay showed direct binding of FOXC1 to Tlr3/4 promoter. Last, a functional study of FOXC1 was performed, which revealed the pro‐inflammatory effects of FOXC1 and its destructive effects on infarct size and heart function in a mouse model of MI. The present study for the first time identified FOXC1 as a novel regulator of Tlr expression and described its function in MI.
Highlights
Ischaemic heart disease is the leading cause of death and disabil‐ ity in most countries worldwide
The present study tried to look for transcription factors (TFs) that regulate Tlr expression in myocardial ischaemia
Forkhead box C1 (FOXC1) was found to act as an ischaemia‐responsive TF that potentially regulates Tlr expression
Summary
Ischaemic heart disease is the leading cause of death and disabil‐ ity in most countries worldwide. The expression of TLR members has been detected in cardiomyocytes, providing novel insights into the inflammatory response initiated by cardiomyocytes themselves.[1] A large number of studies show that TLRs in cardiomyocytes mediate cardiac inflammation and other re‐ sponses to PAMPs and DAMPs. The involvement of cardiac TLRs in myocardial ischaemia has been well documented.[4,5]. Changes of Tlr expression have been observed for myocardial ischaemia, as we reviewed previously.[1] Fallach et al[6] reported in‐ creased immunohistochemical staining for TLR4 in ischaemic mouse heart. To uncover the underlying mechanism stimulating Tlr expression in cardiomy‐ ocytes, the present study screened transcription factors (TFs) that potentially regulate TLR gene transcription, and identified forkhead box C1 (FOXC1) as an ischaemia‐responsive TF that up‐regulates the expression of TLR members in myocardial ischaemia. The present study detected significant increases of FOXC1 in in vivo and in vitro models of myocardial isch‐ aemia and uncovered its regulation on TLR expression
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