Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2

Immunity. 2013 Apr 18;38(4):754-68. doi: 10.1016/j.immuni.2013.02.009. Epub 2013 Mar 7.


Endothelial injury and dysfunction (ED) represent a link between cardiovascular risk factors promoting hypertension and atherosclerosis, the leading cause of death in Western populations. High-density lipoprotein (HDL) is considered antiatherogenic and known to prevent ED. Using HDL from children and adults with chronic kidney dysfunction (HDL(CKD)), a population with high cardiovascular risk, we have demonstrated that HDL(CKD) in contrast to HDL(Healthy) promoted endothelial superoxide production, substantially reduced nitric oxide (NO) bioavailability, and subsequently increased arterial blood pressure (ABP). We have identified symmetric dimethylarginine (SDMA) in HDL(CKD) that causes transformation from physiological HDL into an abnormal lipoprotein inducing ED. Furthermore, we report that HDL(CKD) reduced endothelial NO availability via toll-like receptor-2 (TLR-2), leading to impaired endothelial repair, increased proinflammatory activation, and ABP. These data demonstrate how SDMA can modify the HDL particle to mimic a damage-associated molecular pattern that activates TLR-2 via a TLR-1- or TLR-6-coreceptor-independent pathway, linking abnormal HDL to innate immunity, ED, and hypertension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Arginine / analogs & derivatives
  • Arginine / chemistry
  • Arterial Pressure
  • Atherosclerosis / immunology*
  • Child
  • Endothelium
  • Humans
  • Hypertension / immunology*
  • Immunity, Innate
  • Inflammation Mediators / metabolism
  • Kidney Diseases / immunology*
  • Lipoproteins, HDL / chemistry
  • Lipoproteins, HDL / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide / metabolism
  • Signal Transduction
  • Superoxides / metabolism
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism*
  • Wound Healing


  • Inflammation Mediators
  • Lipoproteins, HDL
  • Toll-Like Receptor 2
  • dimethylarginine
  • Superoxides
  • Nitric Oxide
  • Arginine