Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
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.

PubMed Disclaimer

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

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Maiuolo J., Gliozzi M., Musolino V., Scicchitano M., Carresi C., Scarano F., Bosco F., Nucera S., Ruga S., Zito M.C., et al. The “Frail” Brain Blood Barrier in Neurodegenerative Diseases: Role of Early Disruption of Endothelial Cell-to-Cell Connections. Int. J. Mol. Sci. 2018;19:2693. doi: 10.3390/ijms19092693. - DOI - PMC - PubMed
    1. Lanuti P., Rotta G., Almici C., Avvisati G., Budillon A., Doretto P., Malara N., Marini M., Neva A., Simeone P., et al. Endothelial progenitor cells, defined by the simultaneous surface expression of VEGFR2 and CD133, are not detectable in healthy peripheral and cord blood. Cytom. A. 2016;89:259–270. doi: 10.1002/cyto.a.22730. - DOI - PubMed
    1. Malara N.M., Trunzo V., Musolino G., Aprigliano S., Rotta G., Macrina L., Limongi T., Gratteri S., di Fabrizio E., Renzulli A., et al. Soluble CD54 induces human endothelial cells ex vivo expansion useful for cardiovascular regeneration and tissue engineering application. Int. J. Cardiol. Heart Vasc. 2015;6:48–53. doi: 10.1016/j.ijcha.2015.01.004. - DOI - PMC - PubMed
    1. Di X., Tang X., di X. Montelukast inhibits oxidized low-density lipoproteins (ox-LDL) induced vascular endothelial attachment: An implication for the treatment of atherosclerosis. Biochem. Biophys Res. Commun. 2017;486:58–62. doi: 10.1016/j.bbrc.2017.02.125. - DOI - PubMed
    1. Aw N.H., Canetti E., Suzuki K., Goh J. Monocyte Subsets in Atherosclerosis and Modification with Exercise in Humans. Antioxidants. 2018;19:196. doi: 10.3390/antiox7120196. - DOI - PMC - PubMed