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Review
. 2019 Jul 4;20(13):3294.
doi: 10.3390/ijms20133294.

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

Micaela Gliozzi  1   2 , Miriam Scicchitano  3 , Francesca Bosco  3   4 , Vincenzo Musolino  3   4 , Cristina Carresi  3   4 , Federica Scarano  3 , Jessica Maiuolo  3   4 , Saverio Nucera  3 , Alessia Maretta  3 , Sara Paone  3   4 , Rocco Mollace  3   5 , Stefano Ruga  3 , Maria Caterina Zito  3 , Roberta Macrì  3 , Francesca Oppedisano  3   4 , Ernesto Palma  3   4 , Daniela Salvemini  6 , Carolina Muscoli  3   4   7 , Vincenzo Mollace  8   9   10
Affiliations
Review

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

Micaela Gliozzi et al. Int J Mol Sci. .

Abstract

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Basis for the correlation between dysregulation of eNOS/iNOS enzymes. Uncoupled eNOS is unable to produce NO and generates superoxide anions. The reduction in NO levels and the increase in lipoperoxides upregulate iNOS activity. In this context, lipoperoxide increase causes an enhanced expression of LOX-1 and, consequently, a further dysregulation of NO production.
Figure 2
Figure 2
Mechanisms of NO-release and eNOS regulation.
Figure 3
Figure 3
Proposed mechanism of oxLDL–related endothelial dysfunction via imbalanced regulation of the eNOS/iNOS relationship.
Figure 4
Figure 4
Role of LOX-1 activation in the crosstalk between apoptosis and autophagy in endothelial cells.
See this image and copyright information in PMC

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