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.
Highlights
Endothelial cells (ECs) are the major component of the innermost layer of mammal blood vessels, thereby representing a natural barrier, which functionally serves to maintain the bloodstream separate from extra-vascular tissues
EC dysfunction due to the overproduction of oxidized low-density lipoproteins (oxLDLs) leads to imbalanced activation of nitric oxide synthase (NOS,) expressed constitutively by ECs, thereby facilitating the activation of the inducible isoform of this enzyme, which, in turn, enhances inflammatory processes within the vascular wall and contributes to atherosclerosis progression [6,7,8]
Despite clear evidence suggesting that an imbalanced modulation of eNOS/iNOS derives from high oxLDL production in hyperlipemic patients and that this process underlies some relevant aspects of atherosclerosis progression, the mechanisms through which oxLDLs impair endothelial function, promoting atherosclerosis, remain unclear [9,10]
Summary
Modulation of Nitric Oxide Synthases by Oxidized LDLs: Role in Vascular Inflammation and Atherosclerosis Development. Micaela Gliozzi 1,2,*, Miriam Scicchitano 1, Francesca Bosco 1,2, Vincenzo Musolino 1,2, Cristina Carresi 1,2, Federica Scarano 1, Jessica Maiuolo 1,2, Saverio Nucera 1, Alessia Maretta 1, Sara Paone 1,2, Rocco Mollace 1,3, Stefano Ruga 1, Maria Caterina Zito 1, Roberta Macrì 1, Francesca Oppedisano 1,2, Ernesto Palma 1,2 , Daniela Salvemini 4, Carolina Muscoli 1,2,5 and Vincenzo Mollace 1,2,5,*
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