Abstract 228: Niacin Improves Human Microvascular Endothelial Cell Angiogenic Function Under Lipotoxic and Hypoxic Conditions
Niacin (nicotinic acid) can reduce vascular disease risk, but its mechanism of action is controversial, and may not be dependent on systemic lipid modifying effects. It has recently been shown to improve endothelial function and vascular regeneration, independent of correcting dyslipidemia, in rodent models of vascular injury and ischemia, and metabolic disease. As a potential biosynthetic precursor for NAD+, niacin could elicit vascular benefits through NAD+-dependent, sirtuin (SIRT) mediated responses. Or, it may act through its receptor, GPR109A, to promote endothelial function, though endothelial cells are not known to express this protein. We tested the hypothesis that niacin directly improves endothelial cell function under lipotoxic and low oxygen conditions, and investigated the potential mechanism(s) involved. We measured human microvascular endothelial cell (HMVEC) angiogenic function, by tube formation on Matrigel (18 h), during fatty acid overload (0.5 mM palmitate, oleate, or palmitate plus oleate) under either normoxic (20% O2) or low oxygen (2% O2) conditions. Both supplementation with excess palmitate and incubation at 2% O2 inhibited tube formation compared to control conditions (-38% and -44%, respectively, n=5, p<0.05). Although niacin (10 μM) improved tube formation in the presence of excess palmitate, during both normoxia (35%, n=5, p<0.05) and hypoxia (34%, n=5, p<0.05), it did not increase [NAD+]/[NADH] ratios or SIRT1 activity. Gene expression microarray analyses further showed that niacin did not induce expression of known SIRT1 regulated genes. However, we made the novel observation that HMVEC express GRP109A. Selective activation of the receptor with acifran recapitulated niacin induced improvements in tube formation during palmitate overload in 20% O2 (53%, n=3, p<0.05), while GPR109A siRNA diminished the effect (16%, n=3, p<0.05). We concluded that niacin improves HMVEC angiogenic function under lipotoxic and hypoxic conditions. During normoxia, this effect appears to be independent of NAD+ synthesis and SIRT1 activation, but likely occurs through activation of GPR109A. These findings may have implications for the use of niacin in ischemic vascular disease associated with metabolic disease.
Author Disclosures: D. Pang: None. J. Hughes-Large: None. D. Robson: None. P. Chan: None. N. Borradaile: None.
- © 2014 by American Heart Association, Inc.