Healthy endothelium is essential for undisturbed functioning of the cardiovascular system, while endothelial dysfunction - characterized by the deficiency of vasoprotective mediators such as NO, PGI₂ and EDHF and robust activation of pro-inflammatory and pro-thrombotic phenotype of endothelium - leads to cardiovascular oathologies including atherothrombosis and diabetes. COX-2/PGI₂ pathway represent an important defensive mechanisms of vascular wall. We described that this vasoprotective pathway is stimulated by 1-methylnicotinamide (MNA), a major metabolite of nicotinamide (vitamin PP, vitamin B₃) and MNA afford anti-thrombotic, anti-inflammatory and vasoprotective activity in vitro [1,2] including the ability of MNA to reverse endothelial dysfunction in hypertriglicerydemic and diabetic rats [3] as well as anti-diabetic action [4]. Furthermore, endogenous MNA, produced in the liver from nicotinamide by NNMT (N-nicotinamide-methyl-transferase), as an endogenous activator of COX2/PGI₂ pathway and may play an important regulatory role in the cardiovascular system for example as a compensatory response in atherosclerosis [5] or liver failure [6].

In brief exogenous MNA, displays a unique profile of vasoprotective activity mediated by COX-2/PGI₂ pathway. On the other hand, endogenous MNA, produced in the liver by NNMT, appears to be an endogenous activator of COX2/PGI₂ pathway that may play an important role in the homeostatis of cardiovascular system. Finally, treatment with nicotinic acid provide robust activation of MNA pathway and MNA-dependent mechanisms that may explain some of the pharmacological effects of nicotiinic acid. In conclusion, we propose novel mechanism of vasoprotective activity of nicotinic acid dependent on MNA, and suggest MNA as a prototype stimulator of COX-2/PGI₂ vasoprotective pathway.

[1] K. Bryniarski et al., Eur. J. Pharmacol. 578, 332-338 (2008), [2] S. Chlopicki et al., Br. J. Pharmacol. 152, 230-239 (2007), [3] M. Bartus et al., Pharmacol Rep. 60, 127-138 (2008), [4] C. Watala et al., Pharmacol. Rep.  61, 86-98 (2009), [5] L. Mateuszuk et al., Pharmacol Rep. 61, 76-85 (2009), [6] M. Sternak et al., Pharmacol Rep. 62, 483-493 (2010).

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