Inhibition of MiR-92a May Protect Endothelial Cells After Acute Myocardial Infarction in Rats: Role of KLF2/4

Abstract

BackgroundThis study was designed to investigate the effects of microRNA-92 (miR-92), Kruppel-like factor 2 (KLF2), and Kruppel-like factor 4 (KLF4) on endothelial injury after acute myocardial infarction (AMI).Material/MethodsBlood samples were collected from 50 AMI patients for detection of cardiac troponin I (cTnI), heart-type fatty acid-binding protein (H-FABP), and von Willebrand factor (vWF). The Sprague-Dawley rat models of AMI (n=30) were established by ligating their left anterior descending coronary artery. The cardiac markers of AMI patients and rat models were analyzed with enzyme-linked immunosorbent assay and immunohistochemistry. Human umbilical vein endothelial cells were processed into 5 groups: control, negative control, miR-92a inhibitors, miR-92a inhibitors + KLF2 small interfering RNA (siRNA), and miR-92a inhibitors + KLF4 siRNA. Cell proliferation and apoptosis were detected using MTT assay and flow cytometry. RT-PCR and Western blot were conducted to analyze KLF2 and KLF4 expressions.ResultsAMI patients exhibited significantly higher expression of both endothelial injury markers (e.g., cTnI, H-FABP, vWF) and miR-92a in blood samples, when compared with controls (P<0.05). Model rats also had similar expressional tendencies, along with lower KLF2 and KLF4 expressions (P<0.05). Further, it could be observed in cellular experiments that treatment of miR-92a mimics can further upregulate endothelial injury markers, and miR-92a and both KLF2 and KLF4 were downregulated by miR-92a mimics (all, P<0.05). Also, the luciferase activity assay confirmed the direct binding of miR-92a to 3′ UTR of KLF2/4.ConclusionsMiR-92a was involved in the endothelial injury process after AMI and was able to suppress KLF2 and KLF4 expression.

Silence of miR-32-5p promotes endothelial cell viability by targeting KLF2 and serves as a diagnostic biomarker of acute myocardial infarction

“…Endothelial function is significantly impaired during the progression of AMI, which could be indicated by the inhibited cell viability [22]. For the treatment of AMI, the endothelial activation has been considered as an important signal for the therapeutic efficacy [23], and the explorations of novel molecules that serve as candidate therapeutic targets were performed by investigating the changes in endothelial function [12]. miRNAs are involved in the regulation of cell proliferation, and some members of them have been determined with pivotal roles in AMI pathogenesis by modulating endothelial cell viability [12,22].…”

“…For the treatment of AMI, the endothelial activation has been considered as an important signal for the therapeutic efficacy [23], and the explorations of novel molecules that serve as candidate therapeutic targets were performed by investigating the changes in endothelial function [12]. miRNAs are involved in the regulation of cell proliferation, and some members of them have been determined with pivotal roles in AMI pathogenesis by modulating endothelial cell viability [12,22]. For example, Huang et al reported that miR-103a expression was elevated in AMI patients and involved in the pathogenesis of AMI by regulating the endothelial function, a result manifested by the inhibiting effect of miR-103a on cell proliferation of HUVECs [24].…”

“…The sustained inflammatory response following AMI could contribute to left ventricular dysfunction and remodeling [8], leading to the strategies that attenuate inflammation become efficient therapeutic approaches to improve the clinical outcomes of AMI patients [9]. Kruppel-like factor 2 (KLF2) is a key molecule in angiogenesis and vascular formation [10] and plays a pivotal role in the regulation of endothelial proliferation in AMI [11,12]. A study by Liu et al has reported that KLF2 mediates the effect of miR-92a on endothelial injury in AMI rats [12].…”

“…Kruppel-like factor 2 (KLF2) is a key molecule in angiogenesis and vascular formation [10] and plays a pivotal role in the regulation of endothelial proliferation in AMI [11,12]. A study by Liu et al has reported that KLF2 mediates the effect of miR-92a on endothelial injury in AMI rats [12]. In addition, KLF2 serves an important regulator in the expression of anti-inflammatory genes, thereby involving in the pathogenesis of cardiovascular diseases [13].…”

MicroRNA-145 is involved in endothelial cell dysfunction and acts as a promising biomarker of acute coronary syndrome

“…During the development of ACS, impairments in the function of VECs and the inflammatory response are considered as two important events. Some studies regarding the improvement of the two events have been conducted for the treatment of ACS [25]. For instance, miR-150 has been reported to ameliorate ACS by restoring the function of VECs, such as cell proliferation and migration [26].…”