FRP inhibits ox-LDL-induced endothelial cell apoptosis through an Akt-NF-κB-Bcl-2 pathway and inhibits endothelial cell apoptosis in an apoE-knockout mouse model

Shu Liu, Hua Shen, Ming Xu, Ou Liu, Limin Zhao, Sa Liu, Zhenheng Guo, Jie Du

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Atherosclerosis is the most common cause of cardiovascular diseases in the world. Although the development of atherosclerosis appears to be the result of multiple maladaptive pathways, a particularly important factor in the pathogenesis of atherosclerosis is oxidized low-density lipoprotein (ox-LDL), which contributes to endothelial damage. Data from our laboratory and others show that follistatin-related protein (FRP), which is expressed in the vasculature, has cardioprotective effects, suggesting that loss of FRP protection might play a role in the development of atherosclerosis. In the present study, we determined whether FRP overexpression protects against endothelial cell (EC) damage, an intermediate end point for atherosclerosis. We bred apoE-knockout (apoE-/-) mice that were FRP+ transgenic (they overexpressed FRP). We compared them with control mice (their littermates). Human umbilical vein endothelial cells (HUVECs) were isolated and treated with ox-LDL and recombinant FRP. FRP-induced signal transduction and Bcl-2 mRNA and protein stability were analyzed. After 16 wk, apoE-/- FRP+ mice had significantly fewer apoptotic ECs than controls. In vitro experiments showed that the effect of FRP on EC apoptosis was mediated by upregulation of expression of the antiapoptotic protein Bcl-2. In HUVECs, FRP upregulated Bcl-2 transcription via a PI3K-Akt-NF-κB pathway. We conclude that FRP overexpression maintains EC viability by preventing apoptosis via Bcl-2 upregulation. FRP may be a novel therapeutic target for the prevention and treatment of vascular EC injury and of atherosclerosis.

Original languageEnglish
Pages (from-to)E351-E363
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume299
Issue number3
DOIs
StatePublished - Sep 2010

Keywords

  • Apolipoprotein E
  • Bcl-2
  • Follistatin-related protein
  • Nuclear factor-κB
  • Oxidized low-density lipoprotein

ASJC Scopus subject areas

  • General Medicine

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