Clopidogrel reduces apoptosis and promotes proliferation of human vascular endothelial cells induced by palmitic acid via suppression of the long non-coding RNA HIF1A-AS1 in vitro

Abstract

Cardiovascular disease (CVD) is recognized as a major and increasing health problem affected older subjects in China, and clopidogrel has been widely used for treatment of CVD patients such as atherosclerosis, myocardial infarction, and myocardial ischaemia-reperfusion damage. However, the molecular mechanisms of clopidogrel for treatment of CVD are only partially understood. This study investigated the effects of clopidogrel on palmitic acid-induced damage of human vascular endothelial cells (HUVECs), and the molecular mechanisms of LncRNA HIF1A-AS1 in regulating the proliferation and apoptosis of HUVECs in vitro. We firstly established a damage model of HUVECs through palmitic acid (PA) treatment. And the effect of clopidogrel reducing PA-induced apoptosis of HUVECs was observed by the flow cytometric measurement. To further understand the molecular mechanism of clopidogrel rescues PA-induced apoptosis, we used human LncRNA PCR array to compare the LncRNA expression profile difference between clopidogrel-treated cells and control cells. The expression of LncRNA HIF 1 alpha-antisense RNA 1 (HIF1A-AS1) was significantly altered in clopidogrel-treated cells. We further proved that suppression of HIF1A-AS1 by siRNA reduce PA-induced apoptosis and promote proliferation of HUVECs. Furthermore, we also demonstrated inhibition apoptosis effect by HIF1A-AS1 is related to mitochondrial apoptosis pathway. Hence, our results suggest that clopidogrel rescues apoptosis and promotes proliferation of PA-induced damage model of HUVECs through inhibiting the mediator LncRNA HIF1A-AS1. These findings indicate that LncRNA HIF1A-AS1 may play an important role in the pathogenesis of CVD, and provide a novel molecular mechanism of clopidogrel for treatment of CVD.

Engineered myocardium model to study the roles of HIF-1α and HIF1A-AS1 in paracrine-only signaling under pathological level oxidative stress

“…Most strikingly, we observed that HIF1A-AS1, a recently characterized [34] long non-coding RNA (lncRNA) was downregulated in ECs only, when co-cultured with CMs. Although little is known about HIF1A-AS1, it was shown that suppression of HIF1A-AS1 by siRNA targeting reduced palmitic acid induced apoptosis and promoted proliferation in vascular smooth muscle cells [35, 36] and HUVECs [37] in vitro . The fact that we did not observe any changes in HIF-1α or PHD expression levels might suggest that HIF1A-AS1 may be an alternative means of HIF-1α regulation under oxidative stress.…”

Angio-LncRs: LncRNAs that regulate angiogenesis and vascular disease

“…Palmitic acid (PA) can impose damage to ECs, which is rescued by clopidogrel, an antiplatelet agent widely used for treating cardiovascular disease 95 . LncRNA HIF1α-AS1 was identified as a major lncRNA downregulated by clopidogrel treatment in ECs.…”

“…HIF1α -AS1 was initially identified in VSMCs, and its expression is dependent on BRG1 in VSMCs 97 . Silencing of HIF1α -AS1 has been shown to promote cell proliferation and reduce cell death in VSMCs 95 - 97 . SENCR is a lncRNA enriched in ECs and VSMCs 105 .…”

Long Noncoding RNAs in Atherosclerosis

“…Furthermore, the T variant of rs217727 and the A variant of rs2067051 was associated with increased and decreased risk of CAD, respectively 78) . Moreover, several studies confirm that lncRNA HIF1A-AS1 knockdown decreases apoptosis and promote proliferation VSMC [79][80][81] , but whether it plays a role in atherosclerosis is yet unknown.…”