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Activation of mTOR modulates SREBP-2 to induce foam cell formation through increased retinoblastoma protein

Kun Ling Ma1, Jing Liu, Chang Xian Wang

  • 1Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, NO.87, Ding Jia Qiao Road, Nanjing City, Jiangsu Province 210009, P.R. China.

Cardiovascular Research
|September 27, 2013
PubMed
Abstract

Insights

Inflammation disrupts cholesterol regulation via the mammalian target of rapamycin (mTOR) pathway, increasing lipid accumulation in atherosclerosis. Blocking mTOR with rapamycin or siRNA normalizes cholesterol uptake, even during inflammation.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Cellular Metabolism

Background:

  • Inflammation is a key driver of atherosclerosis, impacting lipid metabolism.
  • The low-density lipoprotein receptor (LDLr) pathway is crucial for cholesterol homeostasis.
  • Mammalian target of rapamycin (mTOR) signaling is implicated in cellular processes relevant to atherosclerosis.

Purpose of the Study:

  • To investigate the role of the mTOR pathway in inflammation-induced disruption of the LDLr pathway.
  • To examine the effects of mTOR inhibition on atherosclerosis in vivo and in vitro.

Main Methods:

  • Atherosclerosis was induced in apolipoprotein E knockout (ApoE KO) mice and rat vascular smooth muscle cells (VSMCs) via inflammation.
  • Lipid accumulation, gene/protein expression (LDLr, SREBP, SCAP, mTOR pathway components), and cell cycle progression were analyzed.
  • Inhibition of mTOR was achieved using rapamycin or small interfering RNA (siRNA).

Main Results:

  • Inflammation increased lipid accumulation in ApoE KO mice aortas and VSMCs.
  • Inflammation enhanced the expression and ER-to-Golgi translocation of SREBP cleavage-activating protein (SCAP)/sterol regulatory element-binding protein (SREBP)-2, alongside increased LDLr expression.
  • Inflammation activated the mTOR pathway, evidenced by increased phosphorylation of retinoblastoma tumor suppressor protein (Rb), mTOR, eukaryotic initiation factor 4E-binding protein 1 (4EBP1), and P70 S6 kinase.
  • mTOR inhibition (rapamycin or siRNA) reduced LDLr, SCAP, and SREBP-2 expression and SCAP/SREBP-2 translocation, mitigating inflammatory effects.

Conclusions:

  • Inflammation disrupts LDLr feedback regulation by activating the mTOR pathway.
  • Activated mTORC1 upregulates SREBP-2-mediated cholesterol uptake through Rb phosphorylation.
  • Targeting the mTOR pathway offers a potential therapeutic strategy for atherosclerosis by modulating cholesterol homeostasis during inflammation.
Keywords:
Foam cell formationInflammationLDL receptor pathwayMammalian target of rapamycin

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