The long noncoding RNA HIF1a-AS1 regulates endothelial cell function and augments in patients with aortic valve disease with coronary artery disease

Ling Zhou (Bonn)1, Y. Zhou (Bonn)1, F. Jansen (Köln)2, S. Zimmer (Bonn)1, G. Nickenig (Bonn)1, M. R. Hosen (Bonn)1

1Universitätsklinikum Bonn Medizinische Klinik und Poliklinik II Bonn, Deutschland; 2Gemeinschaftspraxis Kardiologie Köln am Neumarkt Köln, Deutschland


Long non-coding RNAs (lncRNAs) HIF1a-AS1 is significantly dysregulated in endothelial cells (ECs) and Cardiovascular diseases (CVDs). However, the specific function and the mode of action of the HIF1a-AS1 are still poorly investigated in CVD. Here, we sought to explore the specific role of HIF1a-AS1 in ECs biology and CVD, in addition, to the role of HIF1a in aortic valve stenosis (AVS). HIF1a-AS1 was highly upregulated in aortic valve tissue samples from patients with AVS with coronary artery disease (CAD) compared to healthy controls. small interfering RNA (siRNA) -mediated knockdown of HIF1a-AS1 in ECs increased their effects on cellular function (proliferation, tube formation, angiogenesis). Besides, knockdown HIF1a-AS2 promoted in vitro proliferation of ECs as well. Loss of HIF1a-AS1 promotes THBS1 mRNA and inhibits protein expression. Knockdown of THBS1 by siRNA significantly increased angiogenic capacity (tube formation, proliferation, angiogenesis) in ECs. Furthermore, we found that the expression of HIF1a-AS1 was reduced in normal recipient ECs transwelled with HIF1a-AS1-silenced donor cells. Plus, we also observed that the expression of HIF1a-AS1 was down-regulated in ECs belonging to the group of HIF1a-AS1 downregulated endothelial cell-derived microvesicles (EMVs) group generated from ECs after transfection with HIF1a-AS1 siRNA. Thus, microvesicles (MVs) have the potential to transfer HIF1a-AS1 to recipient cells. These data suggest the transfer of HIF1a-AS1 from HIF1a-AS1-silenced donor cells to the corresponding recipient ECs via MVs. Furthermore, EndMT was successful induction in ECs, but HIF1a-AS1 hardly changed during EndMT. Interestingly, the protein level of THBS1 was different after the knockdown of HIF1a-AS1 in TNF-α-induced EndMT or in TGFβ and IL 1β-induced EndMT. In summary, these data demonstrate that HIF1a-AS1 regulates ECs function via a THBS1-dependent mechanism in
ECs and HIF1a transcription. HIF1a-AS1 is involved in the protein expression of THBS1 under EndMT.

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