Modulation of Nitric Oxide Synthases by Oxidized LDLs: Role in Vascular Inflammation and Atherosclerosis Development

Int J Mol Sci. 2019 Jul 4;20(13):3294. doi: 10.3390/ijms20133294.


The maintenance of physiological levels of nitric oxide (NO) produced by eNOS represents a key element for vascular endothelial homeostasis. On the other hand, NO overproduction, due to the activation of iNOS under different stress conditions, leads to endothelial dysfunction and, in the late stages, to the development of atherosclerosis. Oxidized LDLs (oxLDLs) represent the major candidates to trigger biomolecular processes accompanying endothelial dysfunction and vascular inflammation leading to atherosclerosis, though the pathophysiological mechanism still remains to be elucidated. Here, we summarize recent evidence suggesting that oxLDLs produce significant impairment in the modulation of the eNOS/iNOS machinery, downregulating eNOS via the HMGB1-TLR4-Caveolin-1 pathway. On the other hand, increased oxLDLs lead to sustained activation of the scavenger receptor LOX-1 and, subsequently, to NFkB activation, which, in turn, increases iNOS, leading to EC oxidative stress. Finally, these events are associated with reduced protective autophagic response and accelerated apoptotic EC death, which activates atherosclerotic development. Taken together, this information sheds new light on the pathophysiological mechanisms of oxLDL-related impairment of EC functionality and opens new perspectives in atherothrombosis prevention.

Keywords: constitutive NO synthase cNOS; endothelial dysfunction; inducible NO synthase (iNOS); oxidized LDLs.

Publication types

  • Review

MeSH terms

  • Animals
  • Atherosclerosis / enzymology*
  • Endothelium, Vascular / enzymology*
  • Endothelium, Vascular / pathology*
  • Humans
  • Inflammation / enzymology*
  • Inflammation / pathology
  • Lipoproteins, LDL / metabolism*
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / metabolism*


  • Lipoproteins, LDL
  • oxidized low density lipoprotein
  • Nitric Oxide
  • Nitric Oxide Synthase